Benzhydrol-pyrazole derivatives having kinase inhibitory activity and uses thereof

ABSTRACT

The present invention features benzhydrol-pyrazole derivatives and related compounds having kinase inhibitory activity. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing various medical conditions, such as cancers, inflammatory disorders, or autoimmune disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase of International Application No.PCT/US2013/020834, filed Jan. 9, 2013, which claims benefit of U.S.Provisional Application No. 61/584,569, filed Jan. 9, 2012, which ishereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to benzhydrol-pyrazole derivatives andrelated compounds having kinase inhibitory activity, as well as theirtherapeutic, diagnostic, and medical uses.

Bruton agammaglobulinemia tyrosine kinase (Btk or BTK) is a cytoplasmickinase in the Tec family. Btk plays an important role in the developmentand regulation of lymphoid, myeloid, and mast cell lineages, such as byactivating the B-cell receptor (BCR) signaling pathway, mediatingcytokine receptor signaling, and participating in mast cell activation.However, activation or overactivation of Btk can contribute to orpromote numerous diseases, including B-cell malignancies (e.g.,Hodgkin's lymphoma, non-Hodgkin lymphoma, or chronic lymphocyticleukemia), inflammatory or autoimmune disorders (e.g., rheumatoidarthritis, systemic lupus erythematosus, or multiple sclerosis), andmast cell malignancies (e.g., pancreatic insulinoma). Thus, there is aneed for new compounds that inhibit Btk and treatment methods using suchcompounds.

SUMMARY OF THE INVENTION

The invention features a compound having the formula:

or a stereoisomer, pharmaceutically acceptable salt, or pharmaceuticallyacceptable prodrug thereof,

where

n is an integer from 0 to 4, and each R¹ is, independently, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted halo-C₁₋₆ alkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₂₋₆alkenyloxy, optionally substituted C₂₋₆ alkynyloxy, optionallysubstituted halo-C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkoxy-C₁₋₆alkyl, optionally substituted C₁₋₇ acyl, optionally substituted C₁₋₇acylamino, optionally substituted C₁₋₇ acyloxy, optionally substitutedC₆₋₁₀ aryl, optionally substituted C₁₋₆ alk-C₆₋₁₀ aryl, optionallysubstituted amino, halo, cyano, nitro, hydroxy, or carboxyl;

Ar is optionally substituted C₆₋₁₀ aryl or optionally substituted C₁₋₁₂heteroaryl;

R² is independently, H, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted halo-C₁₋₆ alkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₂₋₆alkenyloxy, optionally substituted C₂₋₆ alkynyloxy, optionallysubstituted halo-C₁₋₆ alkoxy, optionally substituted C₁₋₇ acyl,optionally substituted amino, halo, cyano, nitro, hydroxy, carboxyl, oran N-protecting group;

Y is selected from the group consisting of optionally substituted C₁₋₁₀alkylene, optionally substituted C₁₋₁₀ heteroalkylene, —O—CY¹Y²—,—CY¹Y²—O—, —S—CY¹Y²—, —CY¹Y²—S—, —NY^(N1)—CY¹Y²—, —CY¹Y²—NY^(N1)—, —O—,—S—, —NY^(N1)—, —NY^(N1)—C(O)—, and —C(O)—NY^(N1)—, wherein each Y^(N1)is, independently, H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, or anN-protecting group; and wherein each Y¹ and Y² is, independently, H,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,or optionally substituted C₂₋₆ alkynyl; or wherein the combination of Y¹and Y² can together form oxo or optionally substituted C₁₋₇ spirocyclyl(e.g., Y is —NH—CY¹Y²—, where each Y¹ and Y² is, independently, H oroptionally substituted C₁₋₆ alkyl or where the combination of Y¹ and Y²can together form oxo or optionally substituted C₁₋₇ spirocyclyl);

Z is H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedhalo-C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₂₋₆ alkenyloxy, optionally substituted C₂₋₆ alkynyloxy,optionally substituted halo-C₁₋₆ alkoxy, optionally substituted C₁₋₆alkoxy-C₁₋₆ alkyl, optionally substituted C₁₋₇ acyl, optionallysubstituted C₁₋₇ acylamino, optionally substituted C₁₋₇ acyloxy,optionally substituted C₆₋₁₀ aryl, optionally substituted C₁₋₆ alk-C₆₋₁₀aryl, optionally substituted amino, halo, cyano, nitro, hydroxy, orcarboxyl;

L is optionally substituted C₁₋₁₀ alkylene, optionally substituted C₁₋₁₀heteroalkylene, —NR^(L3)—C(O)—, —C(O)—NR^(L3)—, —NR^(L3)—CR^(L1)R^(L2)—,—CR^(L1)R^(L2)—NR^(L3)—, or a bond, where each R^(L1) and R^(L2) is,independently, H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl; or wherethe combination of R^(L1) and R^(L2) can together form oxo or optionallysubstituted C₁₋₇ spirocyclyl; and where each R^(L3) is, independently,H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, or an N-protecting group(e.g., L is —NH—C(O)—, —C(O)—NH—, —NH—CR^(L1)R^(L2)—,—CR^(L1)R^(L2)—NH—, or a bond, where each R^(L1) and R^(L2) is,independently, H or optionally substituted C₁₋₆ alkyl or where thecombination of R^(L1) and R^(L2) can together form oxo or optionallysubstituted C₁₋₇ spirocyclyl); and

X is optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀ aryl, or optionally substitutedC₁₋₁₂ heterocyclyl.

In some embodiments, n is an integer from 0 to 2; Ar is optionallysubstituted C₆₋₁₀ aryl or optionally substituted C₁₋₁₂ heteroaryl; eachY¹ and Y² is, independently, H or optionally substituted C₁₋₆ alkyl; Zis H, optionally substituted C₁₋₆ alkyl, optionally substitutedhalo-C₁₋₆ alkyl, or halo; L is —NH—C(O)—, —C(O)—NH—, —NH—CR^(L1)R^(L2)—,—CR^(L1)R^(L2)—NH—, or a bond, where each R^(L1) and R^(L2) is,independently, H or optionally substituted C₁₋₆ alkyl; and X isoptionally substituted C₁₋₆ alkyl, optionally substituted C₆₋₁₀ aryl, oroptionally substituted C₁₋₁₂ heterocyclyl.

In some embodiments, the compound has a structure selected from:

or a stereoisomer, pharmaceutically acceptable salt or pharmaceuticallyacceptable prodrug thereof. In particular embodiments, the compound hasthe structure of formula (Ib) or (IIb).

In some embodiments, the compound has a structure selected from:

or a stereoisomer, pharmaceutically acceptable salt or pharmaceuticallyacceptable prodrug thereof, where R¹, R², n, Ar, L, R^(L3), X, Y, Y¹,Y², Y^(N1), Z, if present, are as described herein. In some embodiments,each R², R^(L3), and Y^(N1), is, independently, H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkenyl, or any described herein. In particularembodiments, the compound has the structure of formula (Ib-2) or(IIb-2).

In some embodiments, n is an integer from 0 to 2 (e.g., 0, 1, or 2). Insome embodiments, each R¹ is, independently, optionally substituted C₁₋₆alkyl, optionally substituted halo-C₁₋₆ alkyl, optionally substitutedC₁₋₆ alkoxy, optionally substituted halo-C₁₋₆ alkoxy, optionallysubstituted C₁₋₇ acyl, optionally substituted C₁₋₇ acylamino, optionallysubstituted C₁₋₇ acyloxy, optionally substituted C₆₋₁₀ aryl, optionallysubstituted amino, halo, cyano, nitro, hydroxy, or carboxyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted halo-C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedhalo-C₁₋₆ alkoxy, optionally substituted amino, halo, cyano, nitro,hydroxy, or carboxyl.

In some embodiments, Ar has the formula:

where the combination of R^(a) and R^(b) or the combination of R^(b) andR^(c) can together form optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₁₂ heterocyclyl.

In other embodiments, Ar is optionally substituted C₁₋₁₂ heteroaryl(e.g., selected from the group of optionally substituted phenyl,optionally substituted pyridyl, optionally substituted pyrimidinyl,optionally substituted pyrazinyl, optionally substituted pyridazinyl,optionally substituted naphthyl, optionally substituted indenyl,optionally substituted anthryl, optionally substituted phenanthryl,optionally substituted quinolyl, optionally substituted isoquinolyl,optionally substituted quinoxalinyl, optionally substitutedquinazolinyl, optionally substituted cinnolinyl, optionally substitutedphthalazinyl, and optionally substituted quinolizinyl). In someembodiments, Ar is optionally substituted phenyl, optionally substitutednaphthyl, optionally substituted quinolyl, or optionally substitutedisoquinolyl (e.g., substituted with C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆alkoxy, halo-C₁₋₆ alkoxy, or halo). In other embodiments, Ar isunsubstituted C₁₋₁₂ heteroaryl (e.g., selected from the group of phenyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, indenyl,anthryl, phenanthryl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,cinnolinyl, phthalazinyl, and quinolizinyl).

In some embodiments, each of Y¹, Y², and Z, if present, is,independently, H or optionally substituted C₁₋₆ alkyl, or where thecombination of Y¹ and Y² can together form oxo or spirocyclopropyl. Inparticular embodiments, each of Y¹, Y², and Z is H, or both Y¹ and Y²are H. In some embodiments, Z is H.

In some embodiments, L is —NH—C(O)—, —C(O)—NH—, —NH—CR^(L1)R^(L2)—,—CR^(L1)R^(L2)—NH—, or a bond, where each R^(L1) and R^(L2) is,independently, H, optionally substituted C₁₋₆ alkyl, halo-C₁₋₆ alkyl,C₁₋₆ alkoxy, or halo-C₁₋₆ alkoxy, or where the combination of R^(L1) andR^(L2) can together form oxo or optionally substituted C₁₋₇ spirocyclyl.

In other embodiments, L is —O—CR^(L1)R^(L2)—, —R^(L1)R^(L2)—O—,—S—CR^(L1)R^(L2)—, —CR^(L1)R^(L2)—S—, —NR^(L3)—CR^(L1)R^(L2)—,—CR^(L1)R^(L2)—NR^(L3)—, —O—, —S—, —NR^(L3)—, —NR^(L3)—C(O)—, and—C(O)—NR^(L3)—, wherein each R^(L3) is, independently, H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, or an N-protecting group, and wherein eachR^(L1) and R^(L2) is, independently, H, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, or optionally substitutedC₂₋₆ alkynyl, or wherein the combination of R^(L1) and R^(L2) cantogether form oxo or optionally substituted C₁₋₇ spirocyclyl. In someembodiments, L is selected from the group consisting of optionallysubstituted C₁₋₆ alkylene, —NH—C(O)—, —C(O)—NH—, —NH—CR^(L1)R^(L2)—, and—CR^(L1)R^(L2)NH—, where each R^(L1) and R^(L2) is, independently, H orany described herein (e.g., H or optionally substituted C₁₋₆ alkyl); orwhere the combination of R^(L1) and R^(L2) can together form oxo oroptionally substituted C₁₋₇ spirocyclyl.

In other embodiments, L is optionally substituted C₁₋₁₀ heteroalkylene(e.g., —(CR^(L1)R^(L2))_(LA)—NR^(L3)—(CR^(L1)R^(L2))_(LB)—,—(CR^(L1)R^(L2))_(LA)—O—(CR^(L1)R^(L2))_(LB)—,—(CR^(L1)R^(L2))_(LA)—S—(CR^(L1)R^(L2))_(LB)—,—(CR^(L1)R^(L2))_(LA)—NR^(L3)—C(O)—(CR^(L1)R^(L2))_(LB)—, or—(CR^(L1)R^(L2))_(LA)—NR^(L3)—C(O)—NR^(L3)—(CR^(L1)R^(L2))_(LB)—, whereLA is an integer from 0 to 10, LB is an integer from 0 to 10, and thesum of LA and LB is an integer between 1 to 10 and where R^(L1), R^(L2),and R^(L3) are as described herein). In particular embodiments, L is—(CR^(L1)R^(L2))₀₋₅—NR^(L3)—(CR^(L1)R^(L2))₁₋₅,—(CR^(L1)R^(L2))₁₋₅—NR^(L3)—(CR^(L1)R^(L2))₀₋₅—,—(CR^(L1)R^(L2))₀₋₅—O—(CR^(L1)R^(L2))₁₋₅—,—(CR^(L1)R^(L2))₁₋₅—O—(CR^(L1)R^(L2))₀₋₅—,—(CR^(L1)R^(L2))₀₋₅—S—(CR^(L1)R^(L2))₁₋₅—,—(CR^(L1)R^(L2))₁₋₅—S—(CR^(L1)R^(L2))₀₋₅—,—(CR^(L1)R^(L2))₀₋₅—NR^(L3)—C(O)—(CR^(L1)R^(L2))₁₋₅—,—(CR^(L1)R^(L2))₁₋₅—NR^(L3)—C(O)—(CR^(L1)R^(L2))₀₋₅—,—(CR^(L1)R^(L2))₀₋₅—NR^(L3)—C(O)—NR^(L3)—(CR^(L1)R^(L2))₁₋₅, or—(CR^(L1)R^(L2))₁₋₅—NR^(L3)—C(O)—NR^(L3)—(CR^(L1)R^(L2))₀₋ ₅. In otherembodiments, L is —(CH₂)₀₋₅—NR^(L3)—(CH₂)₁₋₅—,—(CH₂)₁₋₅—NR^(L3)—(CH₂)₀₋₅—, —(CH₂)₀₋₅—O—(CH₂)₁₋₅—, or—(CH₂)₁₋₅—O—(CH₂)₀₋₅—. In further embodiments, each R^(L3) is,independently, H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, or optionally substituted C₂₋₆ alkynyl (e.g.,unsubstituted C₁₋₆ alkyl).

In some embodiments, X is optionally substituted C₆₋₁₀ aryl (e.g.,optionally substituted phenyl, e.g., unsubstituted phenyl or phenylsubstituted with a substituent selected from the group consisting ofC₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, halo, C₁₋₁₂heterocyclyl, (CH₂)_(m)—CO₂R^(X1), —(CH₂)_(m)—C(O)—NR^(X1)R^(X2), and—(CH₂)_(m)—NR^(X1)—C(O)—R^(X2), where m is an integer from 0 to 4 andeach R^(X1) and R^(X2) is, independently, H or optionally substitutedC₁₋₆ alkyl) or optionally substituted C₁₋₁₂ heteroaryl (e.g., selectedfrom the group of optionally substituted quinoxalinyl, optionallysubstituted quinazolinyl, optionally substituted cinnolinyl, optionallysubstituted phthalazinyl, optionally substituted quinolyl, optionallysubstituted isoquinolyl, optionally substituted benzoxazolyl, optionallysubstituted benzimidazolyl, optionally substituted benzothiazolyl,optionally substituted benzothiadiazolyl, optionally substitutedindolyl, optionally substituted indazolyl, optionally substitutedbenzofuranyl, optionally substituted isobenzofuranyl, and optionallysubstituted benzothienyl). In particular embodiments, X is unsubstitutedC₆₋₁₀ aryl (e.g., phenyl, naphthyl, or any described herein) orunsubstituted C₁₋₁₂ heteroaryl (e.g., selected from the group ofquinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinolyl,isoquinolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzothiadiazolyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl,and benzothienyl).

In some embodiments, the compound has a formula provided in Table 1, ora stereoisomer, pharmaceutically acceptable salt, or pharmaceuticallyacceptable prodrug thereof.

In some embodiments, the compound of the invention has an IC₅₀ valueless than about 1.0 μM (e.g., less than about 0.9 μM, less than about0.75 μM, less than about 0.5 μM, less than about 0.3 μM, less than about0.25 μM, less than about 0.2 μM, less than about 0.15 μM, less thanabout 0.1 μM, less than about 0.09 μM, less than about 0.08 μM, lessthan about 0.05 μM, less than about 0.04 μM, less than about 0.03 μM,less than about 0.025 μM, less than about 0.0015 μM, or less than about0.001 μM). In some embodiments, the compound has an IC₅₀ value fromabout 0.02 to about 1.0 μM (e.g., from about 0.02 μM to about 0.9 μM,from about 0.02 μM to about 0.75 μM, from about 0.02 μM to about 0.5 μM,from about 0.02 μM to about 0.3 μM, from about 0.02 μM to about 0.25 μM,from about 0.02 μM to about 0.2 μM, from about 0.02 μM to about 0.15 μM,from about 0.02 μM to about 0.1 μM, from about 0.02 μM to about 0.09 μM,from about 0.02 μM to about 0.08 μM, from about 0.02 μM to about 0.05μM, from about 0.02 μM to about 0.04 μM, from about 0.02 μM to about0.03 μM, or from about 0.02 μM to about 0.025 μM). In some embodiments,the compound has an IC₅₀ value from about 0.0001 μM to about 0.9 μM(e.g., from about 0.0001 μM to about 0.8 μM, from about 0.0001 μM toabout 0.5 μM, from about 0.0001 μM to about 0.3 μM, from about 0.0001 μMto about 0.2 μM, from about 0.0001 μM to about 0.1 μM, from about 0.0001μM to about 0.09 μM, from about 0.0001 μM to about 0.08 μM, from about0.0001 μM to about 0.05 μM, from about 0.0001 μM to about 0.04 μM, fromabout 0.0001 μM to about 0.03 μM, from about 0.0001 μM to about 0.025μM, from about 0.0001 μM to about 0.015 μM, from about 0.0001 μM toabout 0.01 μM, from about 0.0001 μM to about 0.005 μM, 0.0002 μM toabout 0.9 μM, from about 0.0002 μM to about 0.8 μM, from about 0.0002 μMto about 0.5 μM, from about 0.0002 μM to about 0.3 μM, from about 0.0002μM to about 0.2 μM, from about 0.0002 μM to about 0.1 μM, from about0.0002 μM to about 0.09 μM, from about 0.0002 μM to about 0.08 μM, fromabout 0.0002 μM to about 0.05 μM, from about 0.0002 μM to about 0.04 μM,from about 0.0002 μM to about 0.03 μM, from about 0.0002 μM to about0.025 μM, from about 0.0002 μM to about 0.015 μM, from about 0.0002 μMto about 0.01 μM, from about 0.0002 μM to about 0.005 μM, about 0.0005μM to about 0.9 μM, from about 0.0005 μM to about 0.8 μM, from about0.0005 μM to about 0.5 μM, from about 0.0005 μM to about 0.3 μM, fromabout 0.0005 μM to about 0.2 μM, from about 0.0005 μM to about 0.1 μM,from about 0.0005 μM to about 0.09 μM, from about 0.0005 μM to about0.08 μM, from about 0.0005 μM to about 0.05 μM, from about 0.0005 μM toabout 0.04 μM, from about 0.0005 μM to about 0.03 μM, from about 0.0005μM to about 0.025 μM, from about 0.0005 μM to about 0.015 μM, from about0.0005 μM to about 0.01 μM, from about 0.0005 μM to about 0.005 μM, fromabout 0.0005 μM to about 0.002 μM, from about 0.0005 μM to about 0.0015μM, or from about 0.0005 μM to about 0.001 μM).

The invention also features a pharmaceutical composition comprising acompound of formula (I), (I-2), (Ia), (Ia-2), (Ib), (Ib-2), (IIa),(IIa-2), (IIb), or (IIb-2), or a stereoisomer, pharmaceuticallyacceptable salt, or pharmaceutically acceptable prodrug thereof, and apharmaceutically acceptable excipient.

The invention further features a method of treating or prophylacticallytreating a condition in a subject (e.g., a human subject) in needthereof, where the method includes administering an effective amount ofa compound of the invention, or a stereoisomer, pharmaceuticallyacceptable salt, or pharmaceutically acceptable prodrug thereof, or apharmaceutical composition thereof to the subject. Examples of suchconditions include a B-cell associated disease or a mast cell associateddisease (e.g., a cancer, an inflammatory disorder, or an autoimmunedisorder associated with B-cell or mast cell activation), cancer (e.g.,any described herein), or an inflammatory or autoimmune disorder (e.g.,any described herein).

Non-limiting exemplary cancers include leukemia, including acute myeloidleukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloidleukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia,chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia(JMML), and B-cell prolymphocytic leukemia (B-PLL); lymphomas, includingHodgkin and non-Hodgkin lymphoma, such as B-cell lymphomas (e.g.,diffuse large B-cell lymphoma (e.g., mediastinal (thymic) large B-celllymphoma and intravascular large B-cell lymphoma), follicular lymphoma,small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia/smalllymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (e.g., relapsed orrefractory), marginal zone B-cell lymphomas, Burkitt lymphoma,lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervoussystem (CNS) lymphoma, primary effusion lymphoma, and lymphomatoidgranulomatosis); myelomas, including multiple myeloma, plasmacytoma,localized myeloma, and extramedullary myeloma; and other cancers, suchas pancreatic neoplasms, including pancreatic exocrine tumors (e.g.,ductal adenocarcinoma, signet ring cell carcinomas, hepatoid carcinomas,colloid carcinomas, undifferentiated carcinomas, and undifferentiatedcarcinomas with osteoclast-like giant cells), pancreatic cysticneoplasms (e.g., mucinous cystadenoma, serous cystadenoma, and mucinousductal ectasia), pancreatic neuroendocrine tumors (e.g., insulinoma,glucagonoma, gastrinoma, VIPoma, and somatostatinoma), papillary cysticneoplasms of the pancreas, lymphoma of the pancreas, and acinar celltumors of the pancreas, or any described herein.

Non-limiting exemplary inflammatory or autoimmune disorders includeautoimmune arthritis (e.g., rheumatoid arthritis, psoriatic arthritis,ankylosing spondylitis, Still's disease, juvenile arthritis, and mixedand undifferentiated connective tissue diseases), autoimmune hemolyticand thrombocytopenic states (e.g., autoimmune-mediated hemolytic anemia,e.g., warm autoimmune hemolytic anemia, cold autoimmune hemolyticanemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria),autoimmune hepatitis, Behçet's disease, chronic idiopathicthrombocytopenic purpura (ITP), glomerulonephritis, Goodpasture'ssyndrome (and associated glomerulonephritis and pulmonary hemorrhage),idiopathic thrombocytopenic purpura (ITP) (e.g., acute ITP or chronicITP), inflammatory bowel disease (including Crohn's disease andulcerative colitis), multiple sclerosis, psoriasis (including psoriaticlesions in the skin), systemic lupus erythematosus (and associatedglomerulonephritis), and vasculitis (including antineutrophilcytoplasmic antibodies-associated vasculitis, immune complex mediatedvasculitis, and Wegener's granulomatosis), or any described herein.

DEFINITIONS

The term “about,” as used herein, means+/−10% of the recited value.

The term “acyl,” as used herein, represents a hydrogen or an alkyl group(e.g., a haloalkyl group), as defined herein, that is attached to theparent molecular group through a carbonyl group, as defined herein, andis exemplified by formyl (i.e., a carboxyaldehyde group), acetyl,propionyl, butanoyl and the like. Exemplary unsubstituted acyl groupsinclude from 1 to 7 carbons. In some embodiments, the alkyl group isfurther substituted with 1, 2, 3, or 4 substituents as described herein.

The term “acylamino,” as used herein, represents an acyl group, asdefined herein, attached to the parent molecular group though an aminogroup, as defined herein (i.e., N(R^(N1))₂—C(O)—R, where R is H or anoptionally substituted C₁₋₆ alkyl group). Exemplary unsubstitutedacylamino groups include from 1 to 7 carbons. In some embodiments, thealkyl group is further substituted with 1, 2, 3, or 4 substituents asdescribed herein, and/or the amino group is —NH₂ or —NHR^(N1), whereinR^(N1) is, independently, OH, NO₂, NH₂, NR^(N2) ₂, SO₂OR^(N2),SO₂R^(N2), SOR^(N2), alkyl, or aryl, and each R^(N2) can be H, alkyl, oraryl.

The term “acyloxy,” as used herein, represents an acyl group, as definedherein, attached to the parent molecular group though an oxygen atom(i.e., —O—C(O)—R, where R is H or an optionally substituted C₁₋₆ alkylgroup). Exemplary unsubstituted acyloxy groups include from 1 to 7carbons. In some embodiments, the alkyl group is further substitutedwith 1, 2, 3, or 4 substituents as described herein, and/or the aminogroup is —NH₂ or —NHR^(N1), wherein R^(N1) is, independently, OH, NO₂,NH₂, NR^(N2) ₂, SO₂OR^(N2), SO₂R^(N2), SOR^(N2), alkyl, or aryl, andeach R^(N2) can be H, alkyl, or aryl.

The term “alkaryl,” as used herein, represents an aryl group, as definedherein, attached to the parent molecular group through an alkylenegroup, as defined herein. Exemplary unsubstituted alkaryl groups arefrom 7 to 16 carbons (e.g., C₁₋₆ alk-C₆₋₁₀ aryl). In some embodiments,the alkylene and the aryl each can be further substituted with 1, 2, 3,or 4 substituent groups as defined herein for the respective groups.Other groups preceded by the prefix “alk-” are defined in the samemanner, where “alk” refers to a C₁₋₆ alkylene, unless otherwise noted,and the attached chemical structure is as defined herein.

The term “alkcycloalkyl” represents a cycloalkyl group, as definedherein, attached to the parent molecular group through an alkylenegroup, as defined herein (e.g., an alkylene group of 1-4, 1-6, or 1-10carbons). In some embodiments, the alkylene and the cycloalkyl each canbe further substituted with 1, 2, 3, or 4 substituent groups as definedherein for the respective group.

The term “alkenyl,” as used herein, represents monovalent straight orbranched chain groups of, unless otherwise specified, from 2 to 6carbons containing one or more carbon-carbon double bonds and isexemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, and the like. Alkenyl groups may be optionallysubstituted with 1, 2, 3, or 4 substituent groups that are selected,independently, from aryl, cycloalkyl, or heterocyclyl (e.g.,heteroaryl), as defined herein, or any of the exemplary alkylsubstituent groups described herein.

The term “alkenyloxy” represents a chemical substituent of formula —OR,where R is a C₂₋₆ alkenyl group, unless otherwise specified. In someembodiments, the alkenyl group can be further substituted with 1, 2, 3,or 4 substituent groups as defined herein.

The term “alkheteroaryl” refers to a heteroaryl group, as definedherein, attached to the parent molecular group through an alkylenegroup, as defined herein. In some embodiments, the alkylene and theheteroaryl each can be further substituted with 1, 2, 3, or 4substituent groups as defined herein for the respective group.Alkheteroaryl groups are a subset of alkheterocyclyl groups.

The term “alkheterocyclyl” represents a heterocyclyl group, as definedherein, attached to the parent molecular group through an alkylenegroup, as defined herein. Exemplary unsubstituted alkheterocyclyl groupsare from 2 to 18 (e.g., 2 to 17, 2 to 16, 3 to 15, 2 to 14, 2 to 13, or2 to 12) carbons. In some embodiments, the alkylene and the heterocyclyleach can be further substituted with 1, 2, 3, or 4 substituent groups asdefined herein for the respective group.

The term “alkoxy” represents a chemical substituent of formula —OR,where R is a C₁₋₆ alkyl group, unless otherwise specified. In someembodiments, the alkyl group can be further substituted with 1, 2, 3, or4 substituent groups as defined herein.

The term “alkoxyalkyl” represents an alkyl group that is substitutedwith an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups includebetween 2 to 12 carbons (e.g., C₁₋₆ alkoxy-C₁₋₆ alkyl). In someembodiments, the alkyl and the alkoxy each can be further substitutedwith 1, 2, 3, or 4 substituent groups as defined herein for therespective group.

The term “alkyl,” as used herein, is inclusive of both straight chainand branched chain saturated groups from 1 to 6 carbons, unlessotherwise specified. Alkyl groups are exemplified by methyl, ethyl, n-and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like,and may be optionally substituted with one, two, three, or, in the caseof alkyl groups of two carbons or more, four substituents independentlyselected from the group consisting of: (1) C₁₋₆ alkoxy; (2) C₁₋₆alkylsulfinyl; (3) amino; (4) C₆₋₁₀ aryl-C₁₋₆ alkoxy; (5) azido; (6)halo; (7) (C₂₋₉heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g.,carboxyaldehyde or acyl); (11) C₁₋₇ spirocyclyl; (12) thioalkoxy; (13)thiol; (14) —CO₂R^(A′), where R^(A′) is selected from the groupconsisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆alk-C₆₋₁₀ aryl; (15) —C(O)NR^(B′)R^(C′), where each of R^(B′) and R^(C′)is, independently, selected from the group consisting of (a) hydrogen,(b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (16)—SO₂R^(D′), where R^(D′) is selected from the group consisting of (a)C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, and (c) C₁₋₆ alk-C₆₋₁₀ aryl; and (17)—SO₂NR^(E′)R^(F′), where each of R^(E′) and R^(F′) is, independently,selected from the group consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c)C₆₋₁₀ aryl and (d) C₁₋₆ alk-C₆₋₁₀ aryl. In some embodiments, each ofthese groups can be further substituted as described herein. Forexample, the alkylene group of a C₁-alkaryl can be further substitutedwith an oxo group to afford the respective aryloyl substituent.

The term “alkylene” and the prefix “alk-,” as used herein, represent asaturated divalent hydrocarbon group derived from a straight or branchedchain saturated hydrocarbon by the removal of two hydrogen atoms, and isexemplified by methylene, ethylene, isopropylene, and the like. The term“C_(x-y) alkylene” and the prefix “C_(x-y) alk-” represent alkylenegroups having between x and y carbons. Exemplary values for x are 1, 2,3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9,or 10. In some embodiments, the alkylene can be further substituted with1, 2, 3, or 4 substituent groups as defined herein for an alkyl group.

The term “alkylsulfinyl,” as used herein, represents an alkyl groupattached to the parent molecular group through an —S(O)— group.Exemplary unsubstituted alkylsulfinyl groups are from 1 to 6 carbons. Insome embodiments, the alkyl group can be further substituted with 1, 2,3, or 4 substituent groups as defined herein.

The term “alkylsulfinylalkyl,” as used herein, represents an alkylgroup, as defined herein, substituted by an alkylsulfinyl group.Exemplary unsubstituted alkylsulfinylalkyl groups are from 2 to 12carbons. In some embodiments, each alkyl group can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term “alkynyl,” as used herein, represents monovalent straight orbranched chain groups from two to six carbon atoms containing acarbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, andthe like. Alkynyl groups may be optionally substituted with 1, 2, 3, or4 substituent groups that are selected, independently, from aryl,cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, orany of the exemplary alkyl substituent groups described herein.

The term “alkynyloxy” represents a chemical substituent of formula —OR,where R is a C₂₋₆ alkynyl group, unless otherwise specified. In someembodiments, the alkynyl group can be further substituted with 1, 2, 3,or 4 substituent groups as defined herein.

The term “amino,” as used herein, represents N(R^(N1))₂, wherein eachR^(N1) is, independently, H, OH, NO₂, N(R^(N2))₂, SO₂OR^(N2), SO₂R^(N2),SOR^(N2), an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl,alkaryl, cycloalkyl, alkcycloalkyl, heterocyclyl (e.g., heteroaryl),alkheterocyclyl (e.g., alkheteroaryl), or two R^(N1) combine to form aheterocyclyl or an N-protecting group, and wherein each R^(N2) is,independently, H, alkyl, or aryl. The amino groups of the invention canbe an unsubstituted amino (i.e., —NH₂) or a substituted amino (i.e.,—N(R^(N1))₂). In a preferred embodiment, amino is —NH₂ or —NHR^(N1),wherein R^(N1) is, independently, OH, NO₂, NH₂, NR^(N2) ₂, SO₂OR^(N2),SO₂R^(N2), SOR^(N2), alkyl, or aryl, and each R^(N2) can be H, C₁₋₆alkyl, or C₆₋₁₀ aryl.

The term “aminoalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by an amino group, as defined herein. Thealkyl and amino each can be further substituted with 1, 2, 3, or 4substituent groups as described herein for the respective group.

The term “aryl,” as used herein, represents a mono-, bicyclic, ormulticyclic carbocyclic ring system having one or two aromatic rings andis exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like,and may be optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of: (1) C₁₋₇ acyl(e.g., carboxyaldehyde); (2) C₁₋₆ alkyl (e.g., C₁₋₆ alkoxy-C₁₋₆ alkyl,C₁₋₆ alkylsulfinyl-C₁₋₆ alkyl, amino-C₁₋₆ alkyl, azido-C₁₋₆ alkyl,(carboxyaldehyde)-C₁₋₆ alkyl, halo-C₁₋₆ alkyl (e.g., perfluoroalkyl),hydroxy-C₁₋₆ alkyl, nitro-C₁₋₆ alkyl, or C₁₋₆ thioalkoxy-C₁₋₆ alkyl);(3) C₁₋₆ alkoxy (e.g., perfluoroalkoxy); (4) C₁₋₆ alkylsulfinyl; (5)C₆₋₁₀ aryl; (6) amino; (7) C₁₋₆ alk-C₆₋₁₀ aryl; (8) azido; (9) C₃₋₈cycloalkyl; (10) C₁₋₆ alk-C₃₋₈ cycloalkyl; (11) halo; (12) C₁₋₁₂heterocyclyl (e.g., C₁₋₁₂ heteroaryl); (13) (C₁₋₁₂ heterocyclyl)oxy;(14) hydroxy; (15) nitro; (16) C₁₋₆ thioalkoxy; (17)—(CH₂)_(q)CO₂R^(A′), where q is an integer from zero to four, and R^(A′)is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl,(c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18)(CH₂)_(q)CONR^(B′)R^(C′), where q is an integer from zero to four andwhere R^(B′) and R^(C′) are independently selected from the groupconsisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆alk-C₆₋₁₀ aryl; (19) —(CH₂)_(q)SO₂R^(D′), where q is an integer fromzero to four and where R^(D′) is selected from the group consisting of(a) alkyl, (b) C₆₋₁₀ aryl, and (c) alk-C₆₋₁₀ aryl; (20)—(CH₂)_(q)SO₂NR^(E′)R^(F′), where q is an integer from zero to four andwhere each of R^(E′) and R^(F′) is, independently, selected from thegroup consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and(d) C₁₋₆ alk-C₆₋₁₀ aryl; (21) thiol; (22) C₆₋₁₀ aryloxy; (23) C₃₋₈cycloalkoxy; (24) C₆₋₁₀ aryl-C₁₋₆ alkoxy; and (25) C₁₋₆ alk-C₁₋₁₂heterocyclyl (e.g., C₁₋₆ alk-C₁₋₁₂ heteroaryl). In some embodiments,each of these groups can be further substituted as described herein. Forexample, the alkylene group of a C₁-alkaryl or a C₁-alkheterocyclyl canbe further substituted with an oxo group to afford the respectivearyloyl and (heterocyclyl)oyl substituent group.

The term “arylalkoxy,” as used herein, represents an alkaryl group, asdefined herein, attached to the parent molecular group through an oxygenatom. Exemplary unsubstituted arylalkoxy groups are from 7 to 16 carbons(e.g., C₆₋₁₀ aryl-C₁₋₆ alkoxy). In some embodiments, the alkaryl groupcan be substituted with 1, 2, 3, or 4 substituents as defined herein.

The term “aryloxy” represents a chemical substituent of formula OR′,where R′ is an aryl group of 6 to 18 carbons, unless otherwisespecified. In some embodiments, the aryl group can be substituted with1, 2, 3, or 4 substituents as defined herein.

The term “aryloyl,” as used herein, represents an aryl group, as definedherein, that is attached to the parent molecular group through acarbonyl group. Exemplary unsubstituted aryloyl groups are of 7 to 11carbons. In some embodiments, the aryl group can be substituted with 1,2, 3, or 4 substituents as defined herein.

The term “azido” represents an N₃ group, which can also be representedas —N═N═N.

The term “bicyclic,” as used herein, refer to a structure having tworings, which may be aromatic or non-aromatic. Bicyclic structuresinclude spirocyclyl groups, as defined herein, and two rings that shareone or more bridges, where such bridges can include one atom or a chainincluding two, three, or more atoms. Exemplary bicyclic groups include abicyclic carbocyclyl group, where the first and second rings arecarbocyclyl groups, as defined herein; a bicyclic aryl groups, where thefirst and second rings are aryl groups, as defined herein; bicyclicheterocyclyl groups, where the first ring is a heterocyclyl group andthe second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g.,heteroaryl) group; and bicyclic heteroaryl groups, where the first ringis a heteroaryl group and the second ring is a carbocyclyl (e.g., aryl)or heterocyclyl (e.g., heteroaryl) group. In some embodiments, thebicyclic group can be substituted with 1, 2, 3, or 4 substituents asdefined herein for cycloalkyl, heterocyclyl, and aryl groups.

The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to anoptionally substituted C₃₋₁₂ monocyclic, bicyclic, or tricyclicstructure in which the rings, which may be aromatic or non-aromatic, areformed by carbon atoms. Carbocyclic structures include cycloalkyl,cycloalkenyl, and aryl groups.

As used herein, the term “carbamyl” refers to a carbamate group havingthe structure —NR^(N1)C(═O)OR or —OC(═O)N(R^(N1))₂, where the meaning ofeach R^(N1) is found in the definition of “amino” provided herein, and Ris alkyl, cycloalkyl, alkcycloalkyl, aryl, alkaryl, heterocyclyl (e.g.,heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), as definedherein.

The term “carbonyl,” as used herein, represents a C(O) group, which canalso be represented as C═O.

The term “carboxyaldehyde” represents an acyl group having the structureCHO.

The term “carboxyl,” as used herein, means —CO₂H.

The term “cyano,” as used herein, represents an —CN group.

The term “cycloalkyl,” as used herein represents a monovalent saturatedor unsaturated non-aromatic cyclic hydrocarbon group from three to eightcarbons, unless otherwise specified, and is exemplified by cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl,and the like. When the cycloalkyl group includes one carbon-carbondouble bond, the cycloalkyl group can be referred to as a “cycloalkenyl”group. Exemplary cycloalkenyl groups include cyclopentenyl,cyclohexenyl, and the like. The cycloalkyl groups of this invention canbe optionally substituted with: (1) C₁₋₇ acyl (e.g., carboxyaldehyde);(2) C₁₋₆ alkyl (e.g., C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkylsulfinyl-C₁₋₆alkyl, amino-C₁₋₆ alkyl, azido-C₁₋₆ alkyl, (carboxyaldehyde)-C₁₋₆ alkyl,halo-C₁₋₆ alkyl (e.g., perfluoroalkyl), hydroxy-C₁₋₆ alkyl, nitro-C₁₋₆alkyl, or C₁₋₆ thioalkoxy-C₁₋₆ alkyl); (3) C₁₋₆ alkoxy (e.g.,perfluoroalkoxy); (4) C₁₋₆ alkylsulfinyl; (5) C₆₋₁₀ aryl; (6) amino; (7)C₁₋₆ alk-C₆₋₁₀ aryl; (8) azido; (9) C₃₋₈ cycloalkyl; (10) C₁₋₆ alk-C₃₋₈cycloalkyl; (11) halo; (12) C₁₋₁₂ heterocyclyl (e.g., C₁₋₁₂ heteroaryl);(13) (C₁₋₁₂ heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C₁₋₆thioalkoxy; (17) —(CH₂)_(q)CO₂R^(A′), where q is an integer from zero tofour, and R^(A′) is selected from the group consisting of (a) C₁₋₆alkyl, (b) C₆₋₁₀ aryl, (c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18)—(CH₂)_(q)CONR^(B′)R^(C′), where q is an integer from zero to four andwhere R^(B′) and R^(C′) are independently selected from the groupconsisting of (a) hydrogen, (b) C₆₋₁₀ alkyl, (c) C₆₋₁₀ aryl, and (d)C₁₋₆ alk-C₆₋₁₀ aryl; (19) —(CH₂)_(q)SO₂R^(D′), where q is an integerfrom zero to four and where R^(D′) is selected from the group consistingof (a) C₆₋₁₀ alkyl, (b) C₆₋₁₀ aryl, and (c) C₁₋₆ alk-C₆₋₁₀ aryl; (20)—(CH₂)_(q)SO₂NR^(E′)R^(F′), where q is an integer from zero to four andwhere each of R^(E′) and R^(F′) is, independently, selected from thegroup consisting of (a) hydrogen, (b) C₆₋₁₀ alkyl, (c) C₆₋₁₀ aryl, and(d) C₁₋₆ alk-C₆₋₁₀ aryl; (21) thiol; (22) C₆₋₁₀ aryloxy; (23) C₃₋₈cycloalkoxy; (24) C₆₋₁₀ aryl-C₁₋₆ alkoxy; (25) C₁₋₆ alk-C₁₋₁₂heterocyclyl (e.g., C₁₋₆ alk-C₁₋₁₂ heteroaryl); and (26) oxo. In someembodiments, each of these groups can be further substituted asdescribed herein. For example, the alkylene group of a C₁-alkaryl or aC₁-alkheterocyclyl can be further substituted with an oxo group toafford the respective aryloyl and (heterocyclyl)oyl substituent group.

The term “cycloalkoxy,” as used herein, represents a cycloalkyl group,as defined herein, attached to the parent molecular group through anoxygen atom. Exemplary unsubstituted cycloalkoxy groups are from 3 to 8carbons. In some embodiment, the cycloalkyl group can be furthersubstituted with 1, 2, 3, or 4 substituent groups as described herein.

The term “effective amount” of an agent, as used herein, is that amountsufficient to effect beneficial or desired results, for example,clinical results, and, as such, an “effective amount” depends upon thecontext in which it is being applied. For example, in the context ofadministering an agent that treats cancer, an effective amount of anagent is, for example, an amount sufficient to achieve treatment, asdefined herein, of cancer, as compared to the response obtained withoutadministration of the agent.

The term “enantiomer,” as used herein, means each individual opticallyactive form of a compound of the invention, having an optical purity orenantiomeric excess (as determined by methods standard in the art) of atleast 80% (i.e., at least 90% of one enantiomer and at most 10% of theother enantiomer), preferably at least 90% and more preferably at least98%.

The term “halo,” as used herein, represents a halogen selected frombromine, chlorine, iodine, or fluorine.

The term “haloalkoxy,” as used herein, represents an alkoxy group, asdefined herein, substituted by a halogen group (i.e., F, Cl, Br, or I).A haloalkoxy may be substituted with one, two, three, or, in the case ofalkyl groups of two carbons or more, four halogens. Haloalkoxy groupsinclude perfluoroalkoxys (e.g., —OCF₃), —OCHF₂, —OCH₂F, —OCCl₃,—OCH₂CH₂Br, —OCH₂CH(CH₂CH₂Br)CH₃, and —OCHICH₃. In some embodiments, thehaloalkoxy group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkyl groups.

The term “haloalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by a halogen group (i.e., F, Cl, Br, or I).A haloalkyl may be substituted with one, two, three, or, in the case ofalkyl groups of two carbons or more, four halogens. Haloalkyl groupsinclude perfluoroalkyls (e.g., —CF₃), —CHF₂, —CH₂F, —CCl₃, —CH₂CH₂Br,—CH₂CH(CH₂CH₂Br)CH₃, and —CHICH₃. In some embodiments, the haloalkylgroup can be further substituted with 1, 2, 3, or 4 substituent groupsas described herein for alkyl groups.

The term “heteroalkylene,” as used herein, refers to an alkylene group,as defined herein, in which one or two of the constituent carbon atomshave each been replaced by nitrogen, oxygen, and sulfur. In someembodiments, the heteroalkylene group can be further substituted with 1,2, 3, or 4 substituent groups as described herein for alkylene groups.

The term “heteroaryl,” as used herein, represents that subset ofheterocyclyls, as defined herein, which are aromatic: i.e., they contain4n+2 pi electrons within the mono- or multicyclic ring system. Exemplaryunsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10,1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In someembodiment, the heteroaryl is substituted with 1, 2, 3, or 4substituents groups as defined for a heterocyclyl group.

The term “heterocyclyl,” as used herein represents a 5-, 6- or7-membered ring, unless otherwise specified, containing one, two, three,or four heteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur. The 5-membered ring has zero to two doublebonds, and the 6- and 7-membered rings have zero to three double bonds.Exemplary unsubstituted heterocyclyl groups are of 1 to 12 (e.g., 1 to11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. Theterm “heterocyclyl” also represents a heterocyclic compound having abridged multicyclic structure in which one or more carbons and/orheteroatoms bridges two non-adjacent members of a monocyclic ring, e.g.,a quinuclidinyl group. The term “heterocyclyl” includes bicyclic,tricyclic, and tetracyclic groups in which any of the above heterocyclicrings is fused to one, two, or three carbocyclic rings, e.g., an arylring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, acyclopentene ring, or another monocyclic heterocyclic ring, such asindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl,benzothienyl and the like. Examples of fused heterocyclyls includetropanes and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclics includepyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl,morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl,quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzothiadiazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl,triazolyl, tetrazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl), purinyl,thiadiazolyl (e.g., 1,2,3-thiadiazolyl), tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl,dihydroquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl,dihydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl,isobenzofuranyl, benzothienyl, and the like, including dihydro andtetrahydro forms thereof, where one or more double bonds are reduced andreplaced with hydrogens. Still other exemplary heterocyclyls include:2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H-imidazolyl;2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (e.g.,2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl);2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g.,2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl);2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g.,2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl);4,5-dihydro-5-oxo-1H-triazolyl (e.g., 4,5-dihydro-3-methyl-4-amino5-oxo-1H-triazolyl); 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (e.g.,1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl);2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl);1,6-dihydro-6-oxopyridiminyl; 1,6-dihydro-4-oxopyrimidinyl (e.g.,2-(methylthio)-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl);1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g.,1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl);1,6-dihydro-6-oxo-pyridazinyl (e.g.,1,6-dihydro-6-oxo-3-ethylpyridazinyl); 1,6-dihydro-6-oxo-1,2,4-triazinyl(e.g., 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl);2,3-dihydro-2-oxo-1H-indolyl (e.g.,3,3-dimethyl-2,3-dihydro-2-oxo-1H-indolyl and2,3-dihydro-2-oxo-3,3′-spiropropane-1H-indol-1-yl);1,3-dihydro-1-oxo-2H-iso-indolyl; 1,3-dihydro-1,3-dioxo-2H-iso-indolyl;1H-benzopyrazolyl (e.g., 1-(ethoxycarbonyl)-1H-benzopyrazolyl);2,3-dihydro-2-oxo-1H-benzimidazolyl (e.g.,3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl);2,3-dihydro-2-oxo-benzoxazolyl (e.g.,5-chloro-2,3-dihydro-2-oxo-benzoxazolyl);2,3-dihydro-2-oxo-benzoxazolyl; 2-oxo-2H-benzopyranyl;1,4-benzodioxanyl; 1,3-benzodioxanyl; 2,3-dihydro-3-oxo,4H-1,3-benzothiazinyl; 3,4-dihydro-4-oxo-3H-quinazolinyl (e.g.,2-methyl-3,4-dihydro-4-oxo-3H-quinazolinyl);1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl (e.g.,1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl);1,2,3,6-tetrahydro-2,6-dioxo-7H-purinyl (e.g.,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purinyl);1,2,3,6-tetrahydro-2,6-dioxo-1H-purinyl (e.g.,1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purinyl);2-oxobenz[c,d]indolyl; 1,1-dioxo-2H-naphth[1,8-c,d]isothiazolyl; and1,8-naphthylenedicarboxamido. Additional heterocyclics include3,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl, and2,5-diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl),tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl,thiepanyl, azocanyl, oxecanyl, and thiocanyl. Heterocyclic groups alsoinclude groups of the formula

where

E′ is selected from the group consisting of —N— and —CH—; F′ is selectedfrom the group consisting of —N═CH—, —NH—CH₂—, —NH—C(O)—, —NH—, —CH═N—,—CH₂—NH—, —C(O)—NH—, —CH═CH—, —CH₂—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —O—, and—S—; and G′ is selected from the group consisting of —CH— and —N—. Anyof the heterocyclyl groups mentioned herein may be optionallysubstituted with one, two, three, four or five substituentsindependently selected from the group consisting of: (1) C₁₋₇ acyl(e.g., carboxyaldehyde); (2) C₁₋₆ alkyl (e.g., C₁₋₆ alkoxy-C₁₋₆ alkyl,C₁₋₆ alkylsulfinyl-C₁₋₆ alkyl, amino-C₁₋₆ alkyl, azido-C₁₋₆ alkyl,(carboxyaldehyde)-C₁₋₆ alkyl, halo-C₁₋₆ alkyl (e.g., perfluoroalkyl),hydroxy-C₁₋₆ alkyl, nitro-C₁₋₆ alkyl, or C₁₋₆ thioalkoxy-C₁₋₆ alkyl);(3) C₁₋₆ alkoxy (e.g., perfluoroalkoxy); (4) C₁₋₆ alkylsulfinyl; (5)C₆₋₁₀ aryl; (6) amino; (7) C₁₋₆ alk-C₆₋₁₀ aryl; (8) azido; (9) C₃₋₈cycloalkyl; (10) C₁₋₆ alk-C₃₋₈ cycloalkyl; (11) halo; (12) C₁₋₁₂heterocyclyl (e.g., C₂₋₁₂ heteroaryl); (13) (C₁₋₁₂ heterocyclyl)oxy;(14) hydroxy; (15) nitro; (16) C₁₋₆ thioalkoxy; (17)—(CH₂)_(q)CO₂R^(A′), where q is an integer from zero to four, and R^(A′)is selected from the group consisting of (a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl,(c) hydrogen, and (d) C₁₋₆ alk-C₆₋₁₀ aryl; (18)—(CH₂)_(q)CONR^(B′)R^(C′), where q is an integer from zero to four andwhere R^(B′) and R^(C′) are independently selected from the groupconsisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and (d) C₁₋₆alk-C₆₋₁₀ aryl; (19) —(CH₂)_(q)SO₂R^(D′), where q is an integer fromzero to four and where R^(D′) is selected from the group consisting of(a) C₁₋₆ alkyl, (b) C₆₋₁₀ aryl, and (c) C₁₋₆ alk-C₆₋₁₀ aryl; (20)—(CH₂)_(q)SO₂NR^(E′)R^(F′), where q is an integer from zero to four andwhere each of R^(E′) and R^(F′) is, independently, selected from thegroup consisting of (a) hydrogen, (b) C₁₋₆ alkyl, (c) C₆₋₁₀ aryl, and(d) C₁₋₆ alk-C₆₋₁₀ aryl; (21) thiol; (22) C₆₋₁₀ aryloxy; (23) C₃₋₈cycloalkoxy; (24) arylalkoxy; (25) C₁₋₆ alk-C₁₋₁₂ heterocyclyl (e.g.,C₁₋₆ alk-C₁₋₁₂ heteroaryl); (26) oxo; and (27) (C₁₋₁₂heterocyclyl)imino. In some embodiments, each of these groups can befurther substituted as described herein. For example, the alkylene groupof a C₁-alkaryl or a C₁-alkheterocyclyl can be further substituted withan oxo group to afford the respective aryloyl and (heterocyclyl)oylsubstituent group.

The term “(heterocyclyl)imino,” as used herein, represents aheterocyclyl group, as defined herein, attached to the parent moleculargroup through an imino group. In some embodiments, the heterocyclylgroup can be substituted with 1, 2, 3, or 4 substituent groups asdefined herein.

The term “(heterocyclyl)oxy,” as used herein, represents a heterocyclylgroup, as defined herein, attached to the parent molecular group throughan oxygen atom. In some embodiments, the heterocyclyl group can besubstituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term “(heterocyclyl)oyl,” as used herein, represents a heterocyclylgroup, as defined herein, attached to the parent molecular group througha carbonyl group. In some embodiments, the heterocyclyl group can besubstituted with 1, 2, 3, or 4 substituent groups as defined herein.

The term “hydrocarbon,” as used herein, represents a group consistingonly of carbon and hydrogen atoms.

The term “hydroxy,” as used herein, represents an OH group.

The term “hydroxyalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by one to three hydroxy groups, with theproviso that no more than one hydroxy group may be attached to a singlecarbon atom of the alkyl group, and is exemplified by hydroxymethyl,dihydroxypropyl, and the like.

The term “isomer,” as used herein, means any tautomer, stereoisomer,enantiomer, or diastereomer of any compound of the invention. It isrecognized that the compounds of the invention can have one or morechiral centers and/or double bonds and, therefore, exist asstereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers)or diastereomers (e.g., enantiomers (i.e., (+) or (−)) or cis/transisomers). According to the invention, the chemical structures depictedherein, and therefore the compounds of the invention, encompass all ofthe corresponding stereoisomers, that is, both the stereomerically pureform (e.g., geometrically pure, enantiomerically pure, ordiastereomerically pure) and enantiomeric and stereoisomeric mixtures,e.g., racemates. Enantiomeric and stereoisomeric mixtures of compoundsof the invention can typically be resolved into their componentenantiomers or stereoisomers by well-known methods, such as chiral-phasegas chromatography, chiral-phase high performance liquid chromatography,crystallizing the compound as a chiral salt complex, or crystallizingthe compound in a chiral solvent. Enantiomers and stereoisomers can alsobe obtained from stereomerically or enantiomerically pure intermediates,reagents, and catalysts by well-known asymmetric synthetic methods.

The term “N-protected amino,” as used herein, refers to an amino group,as defined herein, to which is attached one or two N-protecting groups,as defined herein.

The term “N-protecting group,” as used herein, represents those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used N-protecting groups are disclosed inGreene, “Protective Groups in Organic Synthesis,” 3^(rd) Edition (JohnWiley & Sons, New York, 1999), which is incorporated herein byreference. N-protecting groups include acyl, aryloyl, or carbamyl groupssuch as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliariessuch as protected or unprotected D, L or D, L-amino acids such asalanine, leucine, phenylalanine, and the like; sulfonyl-containinggroups such as benzenesulfonyl, p-toluenesulfonyl, and the like;carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and thelike, alkaryl groups such as benzyl, triphenylmethyl, benzyloxymethyl,and the like and silyl groups such as trimethylsilyl, and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc),and benzyloxycarbonyl (Cbz).

The term “nitro,” as used herein, represents an —NO₂ group.

The term “oxo” as used herein, represents ═O.

The term “perfluoroalkyl,” as used herein, represents an alkyl group, asdefined herein, where each hydrogen radical bound to the alkyl group hasbeen replaced by a fluoride radical. Perfluoroalkyl groups areexemplified by trifluoromethyl, pentafluoroethyl, and the like.

The term “perfluoroalkoxy,” as used herein, represents an alkoxy group,as defined herein, where each hydrogen radical bound to the alkoxy grouphas been replaced by a fluoride radical. Perfluoroalkoxy groups areexemplified by trifluoromethoxy, pentafluoroethoxy, and the like.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other pharmaceutically acceptable formulation.

A “pharmaceutically acceptable excipient,” as used herein, refers anyingredient other than the compounds described herein (for example, avehicle capable of suspending or dissolving the active compound) andhaving the properties of being substantially nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, and waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A,vitamin E, vitamin C, and xylitol.

The term “pharmaceutically acceptable prodrugs,” as used herein,represents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention.

The term “pharmaceutically acceptable salt,” as use herein, representsthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example,pharmaceutically acceptable salts are described in: Berge et al., J.Pharm. Sci. 66(1):1-19, 1977 and in Pharmaceutical Salts: Properties,Selection, and Use, P. H. Stahl and C. G. Wermuth (eds.), Wiley-VCH,2008. The salts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactingthe free base group with a suitable organic acid. Representative acidaddition salts include acetate, adipate, alginate, ascorbate, aspartate,benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,camphorsulfonate, citrate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like, aswell as nontoxic ammonium, quaternary ammonium, and amine cations,including, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like.

The terms “pharmaceutically acceptable solvate,” as used herein, means acompound of the invention wherein molecules of a suitable solvent areincorporated in the crystal lattice. A suitable solvent isphysiologically tolerable at the dosage administered. For example,solvates may be prepared by crystallization, recrystallization, orprecipitation from a solution that includes organic solvents, water, ora mixture thereof. Examples of suitable solvents are ethanol, water (forexample, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP),dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF),N,N′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU),1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile(ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone,benzyl benzoate, and the like. When water is the solvent, the solvate isreferred to as a “hydrate.”

The term “prodrug,” as used herein, represents compounds that arerapidly transformed in vivo to the parent compound of the above formula,for example, by hydrolysis in blood. Prodrugs of the compounds of theinvention may be conventional esters. Some common esters that have beenutilized as prodrugs are phenyl esters, aliphatic (C₁₋₈ or C₈₋₂₄)esters, cholesterol esters, acyloxymethyl esters, carbamates, and aminoacid esters. For example, a compound of the invention that contains anOH group may be acylated at this position in its prodrug form. Athorough discussion is provided in T. Higuchi and V. Stella, “Pro-drugsas Novel Delivery Systems,” in: Bioreversible Carriers in Drug Design,A.C.S. Symposium Series, Edward B. Roche (ed.), American PharmaceuticalAssociation and Pergamon Press, 1987, vol. 14; and Judkins et al.,Synth. Commun. 26(23):4351-4367, 1996, each of which is incorporatedherein by reference. Preferably, prodrugs of the compounds of thepresent invention are suitable for use in contact with the tissues ofhumans and animals with undue toxicity, irritation, allergic response,and the like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use.

The term “spirocyclyl,” as used herein, represents a C₂₋₇ alkylenediradical, both ends of which are bonded to the same carbon atom of theparent group to form a spirocyclic group, and also a C₁₋₆ heteroalkylenediradical, both ends of which are bonded to the same atom. Theheteroalkylene radical forming the spirocyclyl group can containing one,two, three, or four heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In some embodiments, thespirocyclyl group includes one to seven carbons, excluding the carbonatom to which the diradical is attached. The spirocyclyl groups of theinvention may be optionally substituted with 1, 2, 3, or 4 substituentsprovided herein as optional substituents for cycloalkyl and/orheterocyclyl groups.

The term “stereoisomer,” as used herein, refers to all possibledifferent isomeric as well as conformational forms which a compound maypossess (e.g., a compound of any formula described herein, such asformulas (I), (I-2), (Ia), (Ia-2), (Ib), (Ib-2), (IIa), (IIa-2), (IIb),and (IIb-2)), in particular all possible stereochemically andconformationally isomeric forms, all diastereomers, enantiomers and/orconformers of the basic molecular structure. Some compounds of thepresent invention may exist in different tautomeric forms, all of thelatter being included within the scope of the present invention.

The term “sulfonyl,” as used herein, represents an —S(O)₂— group.

The term “thioalkaryl,” as used herein, represents a chemicalsubstituent of formula SR, where R is an alkaryl group. In someembodiments, the alkaryl group can be further substituted with 1, 2, 3,or 4 substituent groups as described herein.

The term “thioalkheterocyclyl,” as used herein, represents a chemicalsubstituent of formula —SR, where R is an alkheterocyclyl group. In someembodiments, the alkheterocyclyl group can be further substituted with1, 2, 3, or 4 substituent groups as described herein.

The term “thioalkoxy,” as used herein, represents a chemical substituentof formula —SR, where R is an alkyl group. In some embodiments, thealkyl group can be further substituted with 1, 2, 3, or 4 substituentgroups as described herein.

The term “thiol” represents an —SH group.

As used herein, and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, for example,clinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilization (i.e., not worsening) of a state of disease, disorder, orcondition; prevention of spread of disease, disorder, or condition;delay or slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition;remission (whether partial or total), whether detectable orundetectable; and improvement of a disease, disorder, or condition byemploying an agent (e.g., a compound of the invention) in combinationwith another specific agent or therapy directed toward treating thedisease, disorder, or condition. “Palliating” a disease, disorder, orcondition means that the extent and/or undesirable clinicalmanifestations of the disease, disorder, or condition are lessenedand/or time course of the progression is slowed or lengthened, ascompared to the extent or time course in the absence of treatment.“Prophylactically treating” a disease, disorder, or condition means thattreatment is provided to the subject prior to the onset of symptoms ofthe disease, disorder, or condition.

Other features and advantages of the invention will be apparent from thefollowing detailed description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C are spectra for compound 1, including those for NMR (FIG.1A), LC-MS (FIG. 1B), and MS (FIG. 1C) spectroscopy. In FIG. 1B, insettables provide data for each peak [#] in the following order: retentiontime (in minutes, min), type, width (in minutes, min), area, height, andarea (in %).

FIGS. 2A-2B are HPLC spectra for compound 1 at 214 nm (FIG. 2A) and at254 nm (FIG. 2B).

FIGS. 3A-3C are spectra for compound 4, including those for NMR (FIG.3A), LC-MS (FIG. 3B), and MS (FIG. 3C) spectroscopy. In FIG. 3B, insettables provide data for each peak [#] in the following order: retentiontime (in minutes, min), type, width (in minutes, min), area, height, andarea (in %).

FIGS. 4A-4B are HPLC spectra for compound 4 at 214 nm (FIG. 4A) and at254 nm (FIG. 4B).

DETAILED DESCRIPTION

The invention features novel benzhydrol-pyrazole derivatives of formulas(I), (I-2), (Ia), (Ia-2), (Ib), (Ib-2), (IIa), (IIa-2), (IIb), and(IIb-2), and related compounds, having kinase (e.g., BTK) inhibitoryactivity, pharmaceutical and diagnostic compositions containing them,and their medical uses. Exemplary compounds of the invention are shownin Table 1, including stereoisomers (e.g., diastereomers orenantiomers), pharmaceutically acceptable salts, or pharmaceuticallyacceptable prodrugs thereof.

TABLE 1 No. Structure Name 1

N-(4-(2-amino-2-oxoethyl) phenyl)-4-(((2-(hydroxy(phenyl)methyI)phenyl)amino)methyl)- 1H-pyrazole-3-carboxamide 2

(R)-4-(((2-(hydroxy(phenyl) methyl)phenyl)amino)methyl)-N-(3-(2-(methylamino)-2- oxoethyl)phenyl)-1H-pyrazole- 3-carboxamide 3

N-(4-carbamoylphenyl)-4-(((2- (hydroxy(phenyl)methyl)phenyl)amino)methyl)-1H- pyrazole-3-carboxamide 4

4-(((2-(hydroxy(naphthalen-1- yl)methyl)phenyl)amino)methyl)-N-methyl-1H-pyrazole- 3-carboxamide 5

N-(1H-benzo[d]imidazol-6-yl)- 4-(((2-(hydroxy(phenyl)methyl)phenyl)amino)methyl)- 1H-pyrazole-3-carboxamide 6

2-(3-(4-(((2-(hydroxy(phenyl) methyl)phenyl)amino)methyl)-1H-pyrazole-3-carboxamido) phenyl)acetic acid 7

N-(3-carbamoylphenyl)-4-(((2- (hydroxy(phenyl)methyl)phenyl)amino)methyl)- 1H-pyrazole-3-carboxamide 8

4-(((2-(hydroxy(phenyl) methyl)phenyl)amino)methyl)-N-(3-(2-(methylamino)-2- oxoethyl)phenyl)-1H-pyrazole- 3-carboxamide 9

(R)-N-(3-(1H-tetrazol-5-yl) phenyl)-4-(((2-(hydroxy(phenyl)methyl)phenyl)amino)methyl)- 1H-pyrazole-3-carboxamide 10

4-(((2-(hydroxy(phenyl) methyl)phenyl)arnino)methyl)-N-(quinolin-6-yl)-1H-pyrazole- 3-carboxamide 11

N-(3-(1H-tetrazol-5-yl)phenyl)- 4-(((2-(hydroxy(phenyl)methyl)phenyl)amino)methyl)- 1H-pyrazole-3-carboxamide 12

4-(((2-((3-(tert-butyl)phenyl) (hydroxy)methyl) phenyl)amino)methyl)-N-methyl-1H-pyrazole-3- carboxamide 13

4-(((2-(hydroxy(phenyl)methyl) phenyl)amino)methyl)-N-phenyl-1H-pyrazole-3- carboxamide 14

4-(((2-((4-(tert-butyl)phenyl) (hydroxy)methyl)phenyl)amino)methyl)-N-methyl-1H- pyrazole-3-carboxamide 15

4-(((2-(hydroxy(3- (trifluoromethyl)phenyl)methyl)phenyl)amino)methyl)-N- methyl-1H-pyrazole-3- carboxamide 16

4-(((2-(hydroxy(4- (trifluoromethyl)phenyl) methyl)phenyl)amino)methyl)-N-methyl-1H-pyrazole-3- carboxamide 17

4-(((2-(hydroxy(phenyl)methyl) phenyl)amino)methyl)-N-methyl-1H-pyrazole-3- carboxamide 18

4-(((2-(hydroxy(naphthalen-2- yl)methyl)phenyl)amino)methyl)-N-phenyl-1H-pyrazole- 3-carboxamide 19

4-(((2-((4-(tert-butyl)phenyl) (hydroxy)methyl) phenyl)amino)methyl)-N-phenyl-1H-pyrazole-3- carboxamide 20

(4-(4-(((2-(hydroxy(3,4- dichloro-phenyl) methyl)phenyl)amino)methyl)-1H-pyrazole-3-carboxamido) phenyl)carboxylic acid 21

(4-(4-(((2-(hydroxy(7-quinolyl) methyl)phenyl)amino)methyl)-1H-pyrazole-3-carboxamido) phenyl)carboxylic acid 22

N-(4-(1H-tetrazol-4-yl)phenyl)- 4-(((2-(hydroxy(phenyl)methyl)phenyl)amino)methyl)- 1H-pyrazole-3-carboxamide

Exemplary methods for synthesizing compounds of the invention aredescribed herein.

Methods of Preparing Compounds of the Invention

The compounds of the invention can be prepared by processes analogous tothose established in the art, for example, by the reaction sequencesshown in Schemes 1-5. The numbering system used for the general schemesdoes not necessarily correspond to that employed elsewhere in thedescription or in the claims.

A compound of formula E-1 can be prepared under standard reductiveconditions by treating a compound of formula C-1 with a compound offormula D-1, or suitable protected derivatives thereof, and “R” is H,hydroxy, alkyl, alkoxy, or any leaving group, such as chloro, bromo,iodo, or sulfonate (e.g., mesylate, tosylate, or triflate) (see Scheme1). Exemplary reductive conditions include use of borohydride reagents(e.g., NaBH₃CN or NaBH₄) and any other useful conditions describedherein.

A compound of formula G-1 can be prepared by a coupling or acylationreaction between compounds of formulas E-1 and F-1, under standardconditions. For example, if E-1 and F-1 reacts to form an NH—C(O) moiety(e.g., where E-1 includes a carboxy and F-1 includes an amino, asdefined herein, or vice versa), then any of the coupling reactions forpeptides can be used (e.g., as described herein). Alternatively, if thecompound of formula E-1 or F-1 includes an aldehyde or a ketone group,then reductive amination conditions can be used, such as a reducingagent (e.g., NaBH₄, NaBH(OAc)₃, NaCNBH₄, and the like, in an alcoholicsolvent, such as ethanol) or the combination of a silane reagent (e.g.,Et₃SiH, phenylsilanes (e.g., PhSiH₃), halosilanes (e.g.,trichlorosilane), or silylsilanes (e.g., tris(trimethylsilyl)silane)))with catalytic InX₃, FeX₃, CuX, Ni[ligand]₂, PtX₂, Pd[ligand]₂,PdX₂[ligand]₂, or Ir[X(ligand)]₂, where each X is independently halo(e.g., bromo or chloro) and each ligand is any useful ligand (e.g.,1,5-cyclooctadiene, OAc, or PPh₃).

Alternatively, the compounds of the invention can be prepared bymodifying the reactions of Scheme 1 in any useful manner. For example, acompound of formula E-2 can be prepared under standard conditions bytreating a compound of formula C-2 with a compound of formula D-2, orsuitable protected derivatives thereof, and “LG” is a leaving group,such as chloro, bromo, iodo, hydroxy, or sulfonate (e.g., mesylate,tosylate, or triflate) (see Scheme 2). A compound of formula G-2 can beprepared by a coupling or acylation reaction between compounds offormulas E-2 and F-2, under standard conditions, as discussed above forScheme 1.

In addition, the compounds of the invention can be prepared by firstreacting a pyrazolyl derivative with X, as described, e.g., in formula(I) or (Ia), and then reacting the pyrazolyl-X construct with thebenzhydrol derivative core. For example, a compound of formula G-3 canbe prepared under standard reductive conditions (e.g., any describedherein) by treating a compound of formula C-3, or a suitable protectedderivative thereof (e.g., an acetal derivative), with a compound offormula D-3, or a suitable protected derivative thereof, and “R” is H,hydroxy, alkyl, alkoxy, or any leaving group, such as chloro, bromo,iodo, or sulfonate (e.g., mesylate, tosylate, or triflate) (see Scheme3).

Modifications can also be made to the reaction of Scheme 3. For example,a compound of formula G-4 can be prepared by treating a compound offormula C-4, or a suitable protected derivative thereof (e.g., an acetalderivative), with a compound of formula D-4, or a suitable protectedderivative thereof, and “LG” is a leaving group (e.g., any describedherein) (see Scheme 4).

For the reactions in Schemes 1-4, any useful coupling or acylationconditions can be used, such as those used for NH—C(O) coupling inpeptide synthesis. Exemplary coupling reagents include one or more ofthe following reagents: dicyclohexylcarbodiimide (DCC),diisopropylcarbodiimide (DIC), 1-hydroxy-benzotriazole (HOBt),1-hydroxy-7-aza-benzotriazole (HOAt),dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMMCl)either with or without 4-methylmorpholine (NMM),2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) either with or without NMM,O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU),[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazaniumhexafluorophosphate (HCTU),[benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazaniumtetrafluoroborate (TBTU),benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate(PyBOP), chloro(tripyrrolidin-1-yl)phosphanium hexafluorophosphate(PyClop), propylphosphonic anhydride (T3P®),(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU), ethyl (hydroxyimino)cyanoacetate (Oxyma),and O-[(ethoxycarbonyl)cyanomethylen amino]-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HOTU).

The benzhydrol derivative core can be prepared by any useful process.For example, a compound of formula C-5 can be prepared by reacting acompound of formula H-5 with an appropriate Grignard reagent, e.g., acompound of formula J-5, to form an intermediate of formula K-5. Then,the nitro group can be reduced by any useful reductive conditions (e.g.,any described herein, such as Pd/C catalysis) to provide a compound offormula C-5. The amino group of formula C-5 could be further modified(e.g., alkylated) to provide a secondary or tertiary amine.

In some cases the chemistry outlined herein may have to be modified, forinstance, by the use of protective groups to prevent side reactions ofreactive groups, e.g., those attached as substituents. This may beachieved by means of conventional protecting groups as described inProtective Groups in Organic Chemistry, McOmie, Ed., Plenum Press, 1973and in Greene and Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) Edition, 1999.

The compounds of the invention, and intermediates in the preparation ofthe compounds of the invention, may be isolated from their reactionmixtures and purified (if necessary) using conventional techniques,including extraction, chromatography, distillation, andrecrystallization.

The formation of a desired compound salt is achieved using standardtechniques. For example, the neutral compound is treated with an acid ina suitable solvent, and the formed salt is isolated by filtration,extraction, crystallization, or any other suitable method.

The formation of solvates of the compounds of the invention will varydepending on the compound and the solvate. In general, solvates areformed by dissolving the compound in the appropriate solvent andisolating the solvate by cooling or adding an antisolvent. The solvateis typically dried or azeotroped under ambient conditions.

Preparation of an optical isomer of a compound of the invention may beperformed by reaction of the appropriate optically active startingmaterials under reaction conditions which will not cause racemization.Alternatively, the individual enantiomers may be isolated by separationof a racemic mixture using standard techniques, such as, for example,fractional crystallization or chiral HPLC.

A radiolabeled compound of the invention may be prepared using standardmethods known in the art. For example, tritium may be incorporated intoa compound of the invention using standard techniques, such as, forexample, by hydrogenation of a suitable precursor to a compound of theinvention using tritium gas and a catalyst. Alternatively, a compound ofthe invention containing radioactive iodine may be prepared from thecorresponding trialkyltin (suitably trimethyltin) derivative usingstandard iodination conditions, such as [¹²⁵I]sodium iodide in thepresence of chloramine-T in a suitable solvent, such asdimethylformamide. The trialkyltin compound may be prepared from thecorresponding non-radioactive halogen, suitably iodo, compound usingstandard palladium-catalyzed stannylation conditions, such as, forexample, hexamethylditin in the presence of tetrakis(triphenylphosphine)palladium (0) in an inert solvent, such as dioxane, and at elevatedtemperatures, preferably 50-100° C.

Pharmaceutical Uses

The present invention features all uses for compounds of the invention,including use in therapeutic methods. The compounds of the inventionhave useful BTK inhibiting activity, and therefore are useful to treat,prevent, or reduce the risk of, diseases or conditions that areameliorated by a reduction in BTK activity, such as a B-cell relateddisorder or a mast cell related disorder (e.g., any disorder describedherein).

Cancer

BTK is a key regulator in B-cell development, differentiation, andsignaling, as well as in mast cell activation. Accordingly, activationof BTK has been implicated in the pathology of numerous proliferativedisorders, including B-cell, mast cell, and other non-B-cell associatedcancers.

Exemplary proliferative disorders (e.g., cancers) include leukemia,including acute myeloid leukemia (AML), acute lymphocytic leukemia(ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia(CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML),juvenile myelomonocytic leukemia (JMML), and B-cell prolymphocyticleukemia (B-PLL); lymphomas, including Hodgkin and non-Hodgkin lymphoma,such as B-cell lymphomas (e.g., diffuse large B-cell lymphoma (e.g.,mediastinal (thymic) large B-cell lymphoma and intravascular largeB-cell lymphoma), follicular lymphoma, small lymphocytic lymphoma (SLL),chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),mantle cell lymphoma (e.g., relapsed or refractory), marginal zoneB-cell lymphomas (e.g., extranodal marginal zone B-cell lymphoma, nodalmarginal zone B-cell lymphoma, and splenic marginal zone lymphoma),Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrommacroglobulinemia), hairy cell leukemia, primary central nervous system(CNS) lymphoma, primary effusion lymphoma, and lymphomatoidgranulomatosis); myelomas, including multiple myeloma (plasma cellmyeloma), plasmacytoma, localized myeloma, and extramedullary myeloma;and other cancers, such as pancreatic neoplasms, including pancreaticexocrine tumors (e.g., ductal adenocarcinoma, signet ring cellcarcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiatedcarcinomas, and undifferentiated carcinomas with osteoclast-like giantcells), pancreatic cystic neoplasms (e.g., mucinous cystadenoma, serouscystadenoma, and mucinous ductal ectasia), pancreatic neuroendocrinetumors (e.g., insulinoma, glucagonoma, gastrinoma (Zollinger-Ellisonsyndrome), VIPoma, and somatostatinoma), papillary cystic neoplasms ofthe pancreas, lymphoma of the pancreas, and acinar cell tumors of thepancreas; malignant glioma; and papillary thyroid cancer.

Inflammatory Disorders (Including Autoimmune Disorders)

Inhibition of BTK has been shown to mitigate inflammation and/orsuppress the production of inflammatory cytokines. Accordingly, thecompounds of the invention can be used to treat or prophylacticallytreat inflammatory disorders, including autoimmune disorders.

Exemplary inflammatory or autoimmune disorders include rheumatoidarthritis, systemic lupus erythematosus (and associatedglomerulonephritis), multiple sclerosis, and asthma. Further exemplarydisorders include acute disseminated encephalomyelitis, Addison'sdisease, allergy, alopecia universalis, Alzheimer's disease, ankylosingspondylitis, antiphospholipid antibody syndrome, aplastic anemia,appendicitis, atherosclerosis, autoimmune arthritis (e.g., rheumatoidarthritis, psoriatic arthritis, ankylosing spondylitis, Still's disease,juvenile arthritis, and mixed and undifferentiated connective tissuediseases), autoimmune hemolytic and thrombocytopenic states (e.g.,autoimmune-mediated hemolytic anemia, e.g., warm autoimmune hemolyticanemia, cold autoimmune hemolytic anemia, cold agglutinin disease, andparoxysmal cold hemoglobinuria), autoimmune hepatitis, Behçet's disease,blepharitis, bronchiolitis, bronchitis, bursitis, celiac disease,cervicitis, cholangitis, cholecystitis, chronic fatigue, chronicidiopathic thrombocytopenic purpura (ITP), colitis, conjunctivitis,Crohn's disease, cystitis, dacryoadenitis, dermatitis (including contactdermatitis), dermatomyositis, diabetes, dysautonomia, eczema,encephalitis, endocarditis, endometriosis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia(fibrositis), gastritis, gastroenteritis, gingivitis,glomerulonephritis, Goodpasture's syndrome (and associatedglomerulonephritis and pulmonary hemorrhage), Graves' disease,Guillain-Barré syndrome, Hashimoto's thyroiditis, hepatitis,hidradenitis suppurativa, hyperacute rejection of transplanted organs,idiopathic thrombocytopenic purpura (ITP), inflammatory bowel disease(including Crohn's disease and ulcerative colitis), inflammatory pelvicdisease, interstitial cystitis, irritable bowel syndrome, juvenilearthritis, juvenile idiopathic arthritis, laryngitis, mastitis,meningitis, multiple vasculitides, myasthenia gravis, myelitismyocarditis, myocarditis, myositis, nephritis, neuromyotonia,oophoritis, opsoclonus-myoclonus syndrome, optic neuritis, orchitis,Ord's thyroiditis, osteitis, osteoarthritis, osteomyelitis, otitis,pancreatitis, Parkinson's disease, parotitis, pericarditis, peritonitis,pharyngitis, phlebitis, pleuritis, pneumonia, pneumonitis, primarybiliary cirrhosis, proctitis, prostatitis, psoriasis (includingpsoriatic lesions in the skin), psoriatic arthritis, pyelonephritis,Reiter's syndrome, rheumatoid arthritis, rhinitis (including allergicrhinitis), rosacea, salpingitis, scleroderma, septic shock, sinusitis,Sjögren's syndrome, skin sunburn, skin sunburn, Still's disease,stomatitis, synovitis, Takayasu's arteritis, temporal arteritis,tendonitis, tissue graft rejection, tonsillitis, urethritis, urticaria,uveitis, uvitis, vaginitis, vasculitis (including antineutrophilcytoplasmic antibodies-associated vasculitis and immune complex mediatedvasculitis), vulvitis, vulvodynia, warm autoimmune hemolytic anemia, andWegener's granulomatosis.

Combination Formulations and Uses Thereof

The compounds of the invention can be combined with one or moretherapeutic agents. In particular, the therapeutic agent can be one thattreats or prophylactically treats any disorder described herein, such asa B-cell related disorder, cancer, or an inflammatory or autoimmunedisorder.

Combination Formulations

In addition to the formulations described herein, one or more compoundsof the invention can be used in combination with other therapeuticagents. For example, one or more compounds of the invention can becombined with another therapeutic agent. Exemplary therapeutic agentuseful for this purpose include, without limitation, those described inU.S. Pat. Nos. 8,008,309; 7,943,618; 7,884,108; 7,868,018; 7,825,118;7,642,255; 7,501,410; 7,405,295; 6,753,348; and 6,303,652.

In particular embodiments, the compound of the invention is used incombination with an anti-cancer agent or an anti-inflammatory agent(e.g., a nonsteroidal anti-inflammatory drug, acetaminophen, a goldcomplex, a corticosteroid, or an immunosuppressant).

Non-limiting, exemplary anti-cancer agents include fludarabine,cyclophosphamide, methotrexate, rituximab, bendamustine, ofatumumab,dasatinib, U0126((2Z,3Z)-2,3-bis[amino-(2-aminophenyl)sulfanylmethylidene]butanedinitrile),PD98059 (2-(2-amino-3-methoxyphenyl)chromen-4-one), PD184352(2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide),PD0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),ARRY-142886(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),SB 239063(trans-4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanol),SP 600125 (anthra[1-9-cd]pyrazol-6(2H)-one), BAY 43-9006 (sorafenib or4-[4-[[4-chloro-3(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide),wortmannin, or LY 294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one or a hydrochloridesalt thereof). Additional non-limiting, exemplary classes of anti-canceragents include other kinase inhibitors (e.g., a BTK inhibitor, e.g.,PCI-32765(1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),LCB 03-0110((3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol),(−)-terreic acid((1R,6S)-3-hydroxy-4-methyl-7-oxabicyclo[4.1.0]hept-3-ene-2,5-dione),LFM-A13 (2-cyano-N-(2,5-dibromophenyl)-3-hydroxy-2-butenamide),staurosporine, and dasatinib), topoisomerase I inhibitors (e.g.,camptothecin and topotecan), topoisomerase II inhibitors (e.g.,daunomycin and etoposide), alkylating agents (e.g., cyclophosphamide,melphalan, and carmustine (BCNU)), and anti-tubulin agents (e.g., taxoland vinblastine).

Non-limiting, exemplary anti-inflammatory agents include a nonsteroidalanti-inflammatory drug (an NSAID, e.g., non-specific and COX-2 specificcyclooxgenase enzyme inhibitors), acetaminophen, a gold complex, acorticosteroid, and an immunosuppressant. Non-limiting examples ofNSAIDs include acemetacin, aspirin, celecoxib, deracoxib, diclofenac,diflunisal, ethenzamide, etodolac, etofenamate, etoricoxib, fenoprofen,flufenamic acid, flurbiprofen, hydroxychloroquine, ibuprofen,indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, lonazolac,lornoxicam, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam,metamizol, misoprostol, mofebutazone, naproxen, nabumetone, niflumicacid, piroxicam, oxaprozinpiroxicam, oxyphenbutazone, parecoxib,phenidone, phenylbutazone, piroxicam, propacetamol, propyphenazone,rofecoxib, salicylamide, salsalate, sulfasalazine, sulindac, suprofen,tiaprofenic acid, tenoxicam, tolmetin, valdecoxib,4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide,N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide,2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,and2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one.Non-limiting examples of gold complexes include aurothioglucose,auranofin disodium aurothiomalate, sodium aurothiomalate, and sodiumaurothiosulfate. Non-limiting examples of corticosteroids includecortisone, dexamethasone, methylprednisolone, prednisolone, prednisolonesodium phosphate, and prednisone. Non-limiting examples ofimmunosuppressants include alkylation agents (e.g., cyclophosphamide),antimetabolites (e.g., azathioprine, methotrexate, leflunomide, andmycophenolate mofetil), antibodies or antibody fragments or derivatives(e.g., an anti-05 monoclonal antibody, such as eculizumab orpexelizumab; and a TNF antagonist, such as entanercept or infliximab, orfragments or derivatives of any of these), and macrolides (e.g.,cyclosporine and tacrolimus).

Combination Therapies

A compound of the invention can be used alone or in combination withother agents that have BTK-inhibiting activity, or in combination withother types of treatment (which may or may not inhibit BTK) to treat,prevent, and/or reduce the risk of cancer, an inflammatory disorder, orother disorders that benefit from BTK inhibition. In combinationtreatments, the dosages of one or more of the therapeutic compounds maybe reduced from standard dosages when administered alone. For example,doses may be determined empirically from drug combinations andpermutations or may be deduced by isobolographic analysis (e.g., Blacket al., Neurology 65:S3-S6, 2005). In this case, dosages of thecompounds when combined should provide a therapeutic effect.

Pharmaceutical Compositions

The compounds of the invention are preferably formulated intopharmaceutical compositions for administration to human subjects in abiologically compatible form suitable for administration in vivo.Accordingly, in another aspect, the present invention provides apharmaceutical composition comprising a compound of the invention inadmixture with a suitable diluent, carrier, or excipient.

The compounds of the invention may be used in the form of the free base,in the form of salts, solvates, and as prodrugs. All forms are withinthe scope of the invention. In accordance with the methods of theinvention, the described compounds or salts, solvates, or prodrugsthereof may be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds of the invention may be administered,for example, by oral, parenteral, buccal, sublingual, nasal, rectal,patch, pump, or transdermal administration and the pharmaceuticalcompositions formulated accordingly. Parenteral administration includesintravenous, intraperitoneal, subcutaneous, intramuscular,transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topicalmodes of administration. Parenteral administration may be by continuousinfusion over a selected period of time.

A compound of the invention may be orally administered, for example,with an inert diluent or with an assimilable edible carrier, or it maybe enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly with thefood of the diet. For oral therapeutic administration, a compound of theinvention may be incorporated with an excipient and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

A compound of the invention may also be administered parenterally.Solutions of a compound of the invention can be prepared in watersuitably mixed with a surfactant, such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, DMSO and mixtures thereof with or without alcohol, and in oils.Under ordinary conditions of storage and use, these preparations maycontain a preservative to prevent the growth of microorganisms.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003, 20^(th) ed.) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19),published in 1999.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that may be easily administered via syringe.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels, and powders. Aerosol formulations typicallyinclude a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomizing device. Alternatively, the sealed container may bea unitary dispensing device, such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal after use. Where the dosage form comprises an aerosoldispenser, it will contain a propellant, which can be a compressed gas,such as compressed air or an organic propellant, such asfluorochlorohydrocarbon. The aerosol dosage forms can also take the formof a pump-atomizer.

Compositions suitable for buccal or sublingual administration includetablets, lozenges, and pastilles, where the active ingredient isformulated with a carrier, such as sugar, acacia, tragacanth, gelatin,and glycerine. Compositions for rectal administration are convenientlyin the form of suppositories containing a conventional suppository base,such as cocoa butter.

The compounds of the invention may be administered to an animal, e.g., ahuman, alone or in combination with pharmaceutically acceptablecarriers, as noted herein, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration, and standard pharmaceutical practice.

Dosages

The dosage of the compounds of the invention, and/or compositionscomprising a compound of the invention, can vary depending on manyfactors, such as the pharmacodynamic properties of the compound; themode of administration; the age, health, and weight of the recipient;the nature and extent of the symptoms; the frequency of the treatment,and the type of concurrent treatment, if any; and the clearance rate ofthe compound in the animal to be treated. One of skill in the art candetermine the appropriate dosage based on the above factors. Thecompounds of the invention may be administered initially in a suitabledosage that may be adjusted as required, depending on the clinicalresponse. In general, satisfactory results may be obtained when thecompounds of the invention are administered to a human at a daily dosageof, for example, between 0.05 mg and 3000 mg (measured as the solidform). Dose ranges include, for example, between 10-1000 mg (e.g.,50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400,450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of thecompound is administered. Preferred dose ranges include, for example,between 0.05-15 mg/kg or between 0.5-15 mg/kg.

Alternatively, the dosage amount can be calculated using the body weightof the patient. For example, the dose of a compound, or pharmaceuticalcomposition thereof, administered to a patient may range from 0.1-50mg/kg (e.g., 0.25-25 mg/kg). In exemplary, non-limiting embodiments, thedose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0,3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5,7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 mg/kg).

Diagnostic and Screening Assays

In addition to the above-mentioned therapeutic uses, a compound of theinvention can also be used in diagnostic assays, screening assays, andas a research tool.

In diagnostic assays, a compound of the invention may be useful inidentifying or detecting BTK activity.

In screening assays, a compound of the invention may be used to identifyother compounds that inhibit BTK, for example, as first generationdrugs. As research tools, the compounds of the invention may be used inenzyme assays and assays to study the extent of BTK activity. Suchinformation may be useful, for example, for diagnosing or monitoringdisease states or progression. In such assays, a compound of theinvention may also be radiolabeled.

BTK In Vitro Inhibition Assays

The compounds of the present invention have been found to exhibit BTKinhibition. Compounds may be examined for their efficacy in inhibitingkinase activity by a person skilled in the art, for example, by usingthe methods described in Example 1 and the other examples providedherein or by methods known in the literature (e.g., Mast Cells: Methodsand Protocols (eds. G. Krishnaswamy and D.S. Chi), Methods in MolecularBiology, Series 315, Humana Press, pp. 175-192, 2006).

Inhibitory activity can be determined by any useful method. For example,inhibition can be determined by the effect of a test compound on BTKautophosphorylation. Btk and varying concentrations of the test compoundcan be included in a [γ-³²P]ATP-containing kinase buffer.Autophosphorylation can be analyzed by SDS/PAGE followed byelectroblotting and autoradiography, where phosphorylated protein bandscan be quantified by densitometry. These assays can be conducted withoutor with an exogenous substrate (e.g., glutathione S-transferase(GST)-IGα).

In another example, inhibitory activity can be determined by the effectof a test compound on BTK binding. For example, BTK can bind to proteinkinase C (PKC) in vivo, where PKC in turn phosphorylates BTK.Accordingly, an exemplary assay to assess BTK-PKC binding includesincubating PKC or cell lysates having PKC (e.g., lysates from human mastcell lines) with glutathione S-transferase (GST)-Btk beads in theabsence or presence of the test compound. Then, the extent of Btk-boundPKC can be detected by any useful manner, such as by SDS/PAGE followedby immunoblotting with anti-PKC (MC5) and/or anti-BTK antibodies.

Further examples include use of cellular assays, such as by determiningthe effect of a test compound on cellular activation. For example,stimulated lymphoid, myeloid, or mast cells (e.g., cells stimulated witha signaling molecule, such as erythropoietin or an antigen, such as IgE)can be incubated with a test compound, and the activation of particularcompounds or proteins can be measured. Exemplary compounds and proteinsinclude histamine, leukotriene, cytokines, PKC, Janus tyrosine kinase 2(Jak2), erythropoietin receptor (EpoR), Stat5, protein kinase B (PKB),and/or mitogen activating protein kinase (Erk1/2). In another example,as activated Btk can be phosphorylated at tyrosine 223 (Y223) and/ortyrosine 551 (Y551), cellular assays can be conducted by staining P-Y223or P-Y551-positive cells in a population of cells (e.g., byphosphorylation-specific immunochemical staining followed by FACSanalysis).

As BTK is a tyrosine kinase, additional useful assays include anytyrosine kinase assay. In particular, commercially available assaysinclude kinase assays that detect formation of ADP, e.g., withluminescent detection, such as in an ADP-Glo™ Kinase Assay (PromegaCorp., Madison, Wis.).

Dose response curves can be obtained by incubating BTK with a substrate(e.g., ATP or a binding partner, such as PKC) and increasing (e.g.,logarithmically increasing) the concentration of a test compound. Inaddition, a detectable agent (e.g., a luminescent probe, such as aluciferase/luciferin reaction that measures ATP) can be used tocorrelate kinase activity (e.g., ATP-to-ADP conversion) with theconcentration of the test compound. These data can be used to constructa dose response curve, where IC₅₀ is the concentration of the testcompound that provides about 50% inhibition.

The following non-limiting examples are illustrative of the presentinvention.

EXAMPLES Example 1 BTK Assay

The compounds were assayed for BTK inhibition activity using theInvitrogen™ LanthaScreen® Kinase Binding Assay. In short, the compoundswere tested for their ability to displace a tracer (in this caseInvitrogen™ Kinase Tracer 236) from the active site of BTK. The BTKprotein used in the assay was labeled with europium (Eu), and sodisplacement was conveniently detected as a loss of Eu-to-tracer FRET(fluorescence resonance energy transfer) signal using a plate readerequipped to measure TR-FRET (time resolved FRET). This displacementassay is commonly used to characterize kinase inhibitors and it ispredictive of kinase inhibitory activity.

Several of the compounds were also tested directly for kinase inhibitoryactivity using the Invitrogen™ Omnia® assay. The Omnia® assay is a realtime kinetic assay that uses a phosphate-induced fluorophore to detecttransfer of phosphate from ATP to a peptide. Inhibition of kinaseactivity in this assay reduces the rate of fluorescence increase.Compounds tested in both assays demonstrated similar IC₅₀ values. Moredetails and experimental protocols for both assays can be found atinvitrogen.com.

Determination of IC₅₀ Values

Various compounds of the invention (i.e., compounds of formula (Ia))were assayed for BTK inhibition activity, as described above, andpossessed IC₅₀ values less than 1.0 μM. In some embodiments, thecompounds possessed IC₅₀ values less than 0.9 μM, less than 0.75 μM,less than 0.5 μM, less than 0.3 μM, less than 0.25 μM, less than 0.2 μM,less than 0.15 μM, less than 0.1 μM, less than 0.09 μM, less than 0.08μM, less than 0.05 μM, less than 0.04 μM, less than 0.03 μM, or lessthan 0.025 μM. In some embodiments, the compounds possessed IC₅₀ valuesfrom 0.02 μM to 0.9 μM (e.g., from 0.02 μM to 0.75 μM, from 0.02 μM to0.5 μM, from 0.02 μM to 0.3 μM, from 0.02 μM to 0.25 μM, from 0.02 μM to0.2 μM, from 0.02 μM to 0.15 μM, from 0.02 μM to 0.1 μM, from 0.02 μM to0.09 μM, from 0.02 μM to 0.08 μM, from 0.02 μM to 0.05 μM, from 0.02 μMto 0.04 μM, from 0.02 μM to 0.03 μM, or from 0.02 μM to 0.025 μM).

Example 2 Synthesis ofN-(4-(2-amino-2-oxoethyl)phenyl)-4-(((2-(hydroxy(phenyl)methyl)phenyl)amino)methyl)-1H-pyrazole-3-carboxamide(compound 1)

Synthesis of ethyl4-((2-(hydroxy(phenyl)methyl)phenylamino)methyl)-1H-pyrazole-3-carboxylate(1-A)

To a solution of SM1-A (2 g, 11.9 mmol) and SM2-A (2.37 g, 11.9 mmol) in1,2-dichloroethane (DCE, 20 mL) was added acetate acid (1 mL) at roomtemperature (rt). The reaction mixture was stirred at rt for overnight,and then MeOH (10 mL) was added, followed by NaBH₄ (1.9 g, 50 mmol). Thesolution was stirred at rt for another 30 minutes (min); diluted withdichloromethane (DCM, 30 mL); washed with 5% of citric acid (50 mL),NaHCO₃ (sat, 50 mL), and brine (50 mL); dried over Na₂SO₄; andconcentrated and purified by column chromatography (petroleumether:ethyl acetate (PE:EA)=2:1) to give product (1-A) (3.1 g, 74%) as ayellow solid. LC-MS (M+H)⁺=352.

Synthesis of4-((2-(hydroxy(phenyl)methyl)phenylamino)methyl)-1H-pyrazole-3-carboxylicacid (2-A)

To a solution of product (1-A) (1.34 g, 3.8 mmol) in THF (30 mL) wasadded drop-wise a solution of LiOH (0.24 g, 10 mmol) in H₂O (30 mL) at0° C. The reaction mixture was stirred at 50° C. for about 2 h. Aftercooling, ethyl acetate (20 mL) and H₂O (20 mL) were added to thesolution. The aqueous layer was separated and acidified with citric acid(to pH=5) and extracted with ethyl acetate (50 mL×3). The combinedorganic phases were dried over Na₂SO₄ and concentrated to give crudeproduct (2-A) (1.4 g, 100%) as a light yellow solid. LC-MS (M+H)⁺=324.

Synthesis ofN-(4-(2-amino-2-oxoethyl)phenyl)-4-((2-(hydroxy(phenyl)methyl)phenylamino)methyl)-1H-pyrazole-3-carboxamide(compound 1)

To a solution of product (2-A) (200 mg, 0.62 mol) and SM3-A (111 mg,0.74 mmol) in DMF (20 mL) was added2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 350 mg, 0.93 mmol), followed bydiisopropylethylamine (DIPEA, 320 mg, 2.48 mmol) at rt under argon. Thereaction mixture was stirred at rt for overnight. The solvent wasremoved in vacuo and purified by pre-HPLC to give compound 1 (77 mg,27%) as a white solid. ¹H NMR (300 MHz, CD₃OD): δ 7.56-6.69 (M, 14H),5.87 (s, 1H), 4.48 (s, 2H), 3.52 (s, 3H). LC-MS (M+H)⁺=456. ¹H-NMR (inCD₃OD), LC-MS, MS, and HPLC (column: XBridge, 3.5 μm, 2.1×50 mm; mobilephase: H₂O (0.05% trifluoroacetic acid, TFA)-acetonitrile (ACN, 0.05%TFA), ACN from 0% to 60% in seven minutes; total flow rate: 0.8 mL/min)spectroscopy experiments were conducted to provide the data in FIGS.1A-1C and FIGS. 2A-2B for compound 1.

Example 3 Synthesis of4-(((2-(hydroxy(naphthalen-1-yl)methyl)phenyl)amino)methyl)-N-methyl-1H-pyrazole-3-carboxamide(compound 4)

Synthesis of ethyl 2-(2-carbamoylhydrazono)propanoate (1-B)

To a solution of SM2-B (100 g, 0.9 mol) and NaOAc (148 g, 1.8 mol) inwater (1 L) was added drop-wise SM1-B (105 g, 0.9 mol) at rt over 1 h. Awhite precipitate was formed while SM1-B was added. The mixture wasstirred overnight at rt. The precipitate was filtered, washed with H₂O,and dried in air to give crude product (1-B) (200 g, 100%) as a whitesolid. ¹H NMR (300 MHz, d-DMSO): δ 9.88 (s, 1H), 6.50 (br, 2H), 4.20 (q,2H), 2.01 (s, 3H), 1.27 (t, 3H).

Synthesis of ethyl 4-formyl-1H-pyrazole-3-carboxylate (2-B)

POCl₃ (532 mL) was added drop-wise to DMF (1 L) at 0° C. over 1 h. Thesolution was stirred at 0° C. for 1 h, and then product (1-B) (200 g,0.9 mol) was added in small portions while the reaction temperature wasmaintained below 5° C. After the addition, the reaction was heated to80° C. and stirred for another 4 hours. The solution was poured into icewater, and the pH was adjusted to 7 with 2 M NaOH, while maintaining thetemperature below 5° C. After standing overnight, the solid wasfiltered, washed with H₂O, and dried in vacuo to give crude product(2-B) (46 g, 30%, for two steps) as a yellow solid. ¹H NMR (300 MHz,d-DMSO): δ 14.14 (br, 1H), 10.27 (s, 1H), 8.52 (br, 1H), 4.38 (q, 2H),1.35 (t, 3H). LC-MS (M+H)⁺=169.

Synthesis of N-methyl-4-((methylimino)methyl)-1H-pyrazole-3-carboxamide(3-B)

The solution of product (2-B) (16.8 g, 0.1 mol) and MeNH₂ (0.1 L, 0.2mol, 2 N in THF) in MeOH (0.2 L) was stirred overnight at 100° C. in asealed tube. The reaction was monitored by LC-MS until completion. Thesolvent was removed in vacuo to give crude product (3-B) (17.1 g, 100%)as a brown solid. LC-MS (M+H)⁺=167.

Synthesis of 4-formyl-N-methyl-1H-pyrazole-3-carboxamide (3-C)

To a solution of product (3-B) (17.1 g, 0.1 mol) in THF (100 mL) wasadded drop-wise a solution of TFA (57 g, 0.5 mol) in H₂O (100 mL) at rt.The reaction mixture was stirred overnight at rt. The yellow precipitatewas filtered, washed with H₂O, and dried in air to give crude product(3-C) (12.5 g, 82%, for two steps) as a light yellow solid. ¹H NMR (300MHz, d-DMSO): δ 13.93 (br, 1H), 10.33 (br, 1H), 8.52 (br, 1H), 8.44 (s,1H), 2.79 (d, 3H). LC-MS (M+H)⁺=154.

Synthesis of naphthalen-1-yl(2-nitrophenyl)methanol (4-B)

The solution of SM3-B (0.9 g, 6 mmol) in THF (20 mL) was cooled to −78°C., and SM4-B (9 mL, 9 mmol, 1 N in THF) was added drop-wise at −78° C.under argon. The cooling bath was removed, and the reaction was warmedto rt and stirred at rt for overnight. The reaction was quenched bysaturated NH₄Cl (20 mL) and extracted with ethyl acetate (EA, 20 mL x2). The combined organic phases were dried over Na₂SO₄ and concentratedand purified by column chromatography (CC, PE:EA=30:1 to 5:1) to giveproduct (4-B) (0.5 g, 30%) as a yellow oil. LC-MS (M-OH)⁺=262.

Synthesis of (2-aminophenyl)(naphthalen-1-yl)methanol (5-B)

To a solution of product (4-B) (0.5 g 1.8 mmol) in MeOH (20 mL) wasadded Pd(OH)₂/C (0.5 g) at rt. The reaction mixture was stirred at rtunder H₂ for about 1 h until complete consumption of product (4-B) byLC-MS. The reaction mixture was filtered, and the filtrate wasconcentrated to give crude product (5-B) (0.4 g, 90%) as a yellow solid.LC-MS (M-OH)⁺=232.

Synthesis of4-((2-(hydroxy(naphthalen-1-yl)methyl)phenylamino)methyl)-N-methyl-1H-pyrazole-3-carboxamide(compound 4)

To a solution of product (5-B) (0.4 g 1.6 mmol) in DCE (20 mL) was addedproduct (3-C) (0.25 g, 1.6 mmol) at rt under argon. The reaction wasstirred for about 5 h, and then NaBH₃CN (0.5 g, 8 mmol) was added andstirred overnight. The reaction was quenched by saturated NH₄Cl (20 mL)and extracted with DCM/MeOH (20:1 v/v, 20 mL×2). The combined organicphases were dried over Na₂SO₄ and concentrated and purified by Prep-HPLCto give compound 4 (22 mg, 5%) as a white solid. ¹H NMR (300 MHz,d-DMSO): δ 13.04 (br, 1H), 8.14-7.32 (m, 9H), 7.04-6.36 (m, 4H),5.98-5.85 (m, 2H), 4.47 (d, 2H), 2.72 (d, 3H). LC-MS (M+H)⁺=387. ¹H-NMR(in DMSO), LC-MS, MS, and HPLC (column: Thermo, 2.4 μm, 4.6×100 mm;mobile phase: H₂O (0.05% TFA)-ACN (0.05% TFA), ACN from 10% to 100% ineight minutes; total flow rate: 1.0 mL/min) spectroscopy experimentswere conducted to provide the data in FIGS. 3A-3C and FIGS. 4A-4B forcompound 4.

Other Embodiments

While the present invention has been described with reference to whatare presently considered to be the preferred examples, it is to beunderstood that the invention is not limited to the disclosed examples.To the contrary, the invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. Where a term in the present application is found to bedefined differently in a document incorporated herein by reference, thedefinition provided herein is to serve as the definition for the term.

Other embodiments are in the claims.

What is claimed is:
 1. A compound having the formula:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein nis an integer from 0 to 4, and each R¹ is, independently, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted halo-C₁₋₆ alkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₂₋₆alkenyloxy, optionally substituted C₂₋₆ alkynyloxy, optionallysubstituted halo-C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkoxy-C₁₋₆alkyl, optionally substituted C₁₋₇ acyl, optionally substituted C₁₋₇acylamino, optionally substituted C₁₋₇ acyloxy, optionally substitutedC₆₋₁₀ aryl, optionally substituted C₁₋₆ alk-C₆₋₁₀ aryl, optionallysubstituted amino, halo, cyano, nitro, hydroxy, or carboxyl; Ar isoptionally substituted C₆₋₁₀ aryl or optionally substituted C₁₋₁₂heteroaryl; R² is independently, H, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted halo-C₁₋₆alkyl, optionally substituted C₁₋₆ alkoxy, optionally substituted C₂₋₆alkenyloxy, optionally substituted C₂₋₆ alkynyloxy, optionallysubstituted halo-C₁₋₆ alkoxy, optionally substituted C₁₋₇ acyl,optionally substituted amino, halo, cyano, nitro, hydroxy, carboxyl, oran N-protecting group; Y is —CY¹Y²—NY^(N1)-, wherein each Y^(N1) is,independently, H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, or anN-protecting group; and wherein each Y¹ and Y² is, independently, H,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,or optionally substituted C₂₋₆ alkynyl; or wherein the combination of Y¹and Y² can together form oxo or optionally substituted C₁₋₇ spirocyclyl;Z is H, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedhalo-C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₂₋₆ alkenyloxy, optionally substituted C₂₋₆ alkynyloxy,optionally substituted halo-C₁₋₆ alkoxy, optionally substituted C₁₋₆alkoxy-C₁₋₆ alkyl, optionally substituted C₁₋₇ acyl, optionallysubstituted C₁₋₇ acylamino, optionally substituted C₁₋₇ acyloxy,optionally substituted C₆₋₁₀ aryl, optionally substituted C₁₋₆ alk-C₆₋₁₀aryl, optionally substituted amino, halo, cyano, nitro, hydroxy, orcarboxyl; L is optionally substituted C₁₋₁₀ alkylene, optionallysubstituted C₁₋₁₀ heteroalkylene, —NR^(L3)—C(O)—, —C(O)—NR^(L3)—,—NR^(L3)—CR^(L1)R^(L2)—, —CR^(L1)R^(L2)NR^(L3)—, or a bond, wherein eachR^(L1) and R^(L2) is, independently, H, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl; or wherein the combination of R^(L1) and R^(L2) can togetherform oxo or optionally substituted C₁₋₇ spirocyclyl; and wherein eachR^(L3) is, independently, H, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, or an N-protecting group; and X is optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₈ cycloalkyl, optionally substitutedC₆₋₁₀ aryl, or optionally substituted C₁₋₁₂ heterocyclyl.
 2. Thecompound of claim 1, wherein n is an integer from 0 to 2; Ar isoptionally substituted C₆₋₁₀ aryl or optionally substituted C₁₋₁₂heteroaryl; each Y¹ and Y² is, independently, H or optionallysubstituted C₁₋₆ alkyl; Z is H, optionally substituted C₁₋₆ alkyl,optionally substituted halo-C₁₋₆ alkyl, or halo; L is —NH—C(O)—,—C(O)—NH—, —NH—CR^(L1)R^(L2)—, —CR^(L1)R^(L2)—NH—, or a bond, whereineach R^(L1) and R^(L2) is, independently, H or optionally substitutedC₁₋₆ alkyl; and X is optionally substituted C₁₋₆ alkyl, optionallysubstituted C₆₋₁₀ aryl, or optionally substituted C₁₋₁₂ heterocyclyl. 3.The compound of claim 1, wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein said compound has the formula:

or a stereoisomer or pharmaceutically acceptable salt thereof.
 6. Thecompound of claim 1, wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein n is
 0. 8. The compound of claim 1, wherein Ar has theformula:

and wherein the combination of R^(a) and R^(b) or the combination ofR^(b) and R^(c) can together form optionally substituted C₆₋₁₀ aryl oroptionally substituted C₁₋₁₂ heterocyclyl.
 9. The compound of claim 1,wherein Ar is optionally substituted C₁₋₁₂ heteroaryl.
 10. The compoundof claim 1, wherein Ar is selected from the group consisting ofoptionally substituted phenyl, optionally substituted pyridyl,optionally substituted pyrimidinyl, optionally substituted pyrazinyl,optionally substituted pyridazinyl, optionally substituted naphthyl,optionally substituted indenyl, optionally substituted anthryl,optionally substituted phenanthryl, optionally substituted quinolyl,optionally substituted isoquinolyl, optionally substituted quinoxalinyl,optionally substituted quinazolinyl, optionally substituted cinnolinyl,optionally substituted phthalazinyl, and optionally substitutedquinolizinyl.
 11. The compound of claim 10, wherein Ar is optionallysubstituted phenyl, optionally substituted naphthyl, optionallysubstituted quinolyl, or optionally substituted isoquinolyl.
 12. Thecompound of claim 11, wherein Ar is substituted with C₁₋₆ alkyl,halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, or halo.
 13. Thecompound of claim 1, wherein each of Y¹, Y², and Z, if present, is,independently, H or optionally substituted C₁₋₆ alkyl, or wherein thecombination of Y¹ and Y² can together form oxo or spirocyclopropyl. 14.The compound of claim 1, wherein X is optionally substituted C₆₋₁₀ arylor optionally substituted C₁₋₁₂ heteroaryl.
 15. The compound of claim14, wherein X is optionally substituted phenyl.
 16. The compound ofclaim 15, wherein X is unsubstituted phenyl or phenyl substituted with asubstituent selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, halo, C₁₋₁₂ heterocyclyl,—(CH₂)_(m)—CO₂R^(X1), —(CH₂)_(m)—C(O)—NR^(X1)R^(X2), and—(CH₂)_(m)—NR^(X1)—C(O)—R^(X2), wherein m is an integer from 0 to 4 andeach R^(X1) and R^(X2) is, independently, H or optionally substitutedC₁₋₆ alkyl.
 17. The compound of claim 14, wherein X is selected from thegroup consisting of optionally substituted quinoxalinyl, optionallysubstituted quinazolinyl, optionally substituted cinnolinyl, optionallysubstituted phthalazinyl, optionally substituted quinolyl, optionallysubstituted isoquinolyl, optionally substituted benzoxazolyl, optionallysubstituted benzimidazolyl, optionally substituted benzothiazolyl,optionally substituted benzothiadiazolyl, optionally substitutedindolyl, optionally substituted indazolyl, optionally substitutedbenzofuranyl, optionally substituted isobenzofuranyl, and optionallysubstituted benzothienyl.
 18. A compound having the formula:

or a stereoisomer or pharmaceutically acceptable salt thereof.
 19. Apharmaceutical composition comprising the compound of claim 1, or astereoisomer, pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 20. A method of inhibitingBruton's tyrosine kinase (BTK) in a subject in need thereof, whereinsaid method comprises administering an effective amount of the compoundof claim 1, or a stereoisomer, pharmaceutically acceptable salt, orpharmaceutical composition thereof to said subject.
 21. A method oftreating lymphoma in a subject in need thereof by inhibiting Bruton'styrosine kinase (BTK), said method comprising administering an effectiveamount of a compound of claim 1, or a stereoisomer, pharmaceuticallyacceptable salt, or pharmaceutical composition thereof, to said subject.22. The method of claim 21, wherein said lymphoma is non-Hodgkinlymphoma, B-cell lymphoma, or small lymphocytic lymphoma.